Phosphonate analogs for treating metabolic diseases

ABSTRACT

The invention is related to phosphorus substituted compounds with activity for treating metabolic diseases and/or disorders, e.g., diabetes and hypercholesterolemia, compositions containing such compounds, and therapeutic methods that include the administration of such compounds, as well as to processes and intermediates useful for preparing such compounds.

PRIORITY OF INVENTION

This application claims the benefit of priority under 35 U.S.C. § 119(e)to U.S. Provisional Patent Application Ser. Nos. 60/465,536, 60/465,763,60/465,339, 60/465,292, 60/465,399, 60/465,355, 60/465,751, 60/465,317,60/465,689, 60/465,475, 60/465,325, and 60/465,286, all filed Apr. 25,2003; to U.S. Provisional Patent Application Ser. Nos. 60/495,753,60/495,681, 60/495,534, 60/495,347, 60/495,762, 60/495,526, 60/495,361,60/495,354, 60/495,683, 60/495,489, 60/495,669, and 60/495,531, allfiled Aug. 15, 2003; to U.S. Provisional Patent Application Ser. Nos.60/513,954, 60/513,966, 60/514,465, 60/514,303, and 60/514,104, allfiled Oct. 24, 2003; to U.S. Provisional Patent Application Ser. Nos.60/532,273, 60/532,184, 60/532,183 and 60/532,274, all filed Dec. 22,2003; to U.S. Provisional Patent Application Ser. Nos. 60/532,683,60/532,682, 60/532,587 and 60/532,415, all filed Dec. 23, 2003; and toU.S. Provisional Patent Application Ser. No. 60/536,179, filed Jan. 12,2004. The entirety of all Provisional Applications listed above areincorporated herein by reference.

FIELD OF THE INVENTION

The invention relates generally to compounds with activity for treatingmetabolic diseases and/or disorders, e.g., diabetes andhypercholesterolemia.

BACKGROUND OF THE INVENTION

Improving the delivery of drugs and other agents to target cells andtissues has been the focus of considerable research for many years.Though many attempts have been made to develop effective methods forimporting biologically active molecules into cells, both in vivo and invitro, none has proved to be entirely satisfactory. Optimizing theassociation of the inhibitory drug with its intracellular target, whileminimizing intercellular redistribution of the drug, e.g., toneighboring cells, is often difficult or inefficient.

Most agents currently administered to a patient parenterally are nottargeted, resulting in systemic delivery of the agent to cells andtissues of the body where it is unnecessary, and often undesirable. Thismay result in adverse drug side effects, and often limits the dose of adrug (e.g., glucocorticoids and other anti-inflammatory drugs) that canbe administered. By comparison, although oral administration of drugs isgenerally recognized as a convenient and economical method ofadministration, oral administration can result in either (a) uptake ofthe drug through the cellular and tissue barriers, e.g., blood/brain,epithelial, cell membrane, resulting in undesirable systemicdistribution, or (b) temporary residence of the drug within thegastrointestinal tract. Accordingly, a major goal has been to developmethods for specifically targeting agents to cells and tissues. Benefitsof such treatment includes avoiding the general physiological effects ofinappropriate delivery of such agents to other cells and tissues, suchas uninfected cells.

Statins lower plasma cholesterol level by decreasing hepatic cholesterolbiosynthesis and by upregulating low-density lipoprotein (LDL) receptorson hepatocytes. Their side effects, such as gastrointestinal discomfort,headache, rash and elevations in serum transaminase activity (a sign ofhepatotoxicity) have been the principal problems preventing their usage.

Pitavastatin (U.S. Pat. No. 5,856,336), Rosuvastatin (Crestor) (U.S.Pat. No. RE37314 and U.S. Pat. No. 5,260,440), Pravastatin (U.S. Pat.No. 4,346,227), Fluvastatin (U.S. Pat. Nos. 5,354,772 and 4,739,073),Lovastatin and Sivastatin (mevalonate analogs; U.S. Pat. Nos. 4,231,938and 4,444,784), Cerivastatin (a substituted pyridine; U.S. Pat. No.5,006,530) are members of the statin class of HMG-CoA reductaseinhibitors used as oral treatments for hypercholesterolemia anddyslipidemia. They are structural analogs of the half-reducedintermediate of HMG-CoA and, as such, inhibit the formation ofmevalonate.

Compounds such as Pitavastatin and its opened chain form are useful forinhibiting chloesterol biosynthesis and lowering blood cholesterollevels and, as such, are useful in the treatment of atherosclerosishypercholesterolemia and hyper lipoproteinemia as described in U.S. Pat.No. 5,856,336.

Certain triaryl ethylenes are useful in the treatment ofhypercholesterolemia and osteoporosis by acting as selective estrogenreceptor modulators. One such derivative, Ospemifene, is described inWO01/36360.

Certain 2,6-dialkylated phenols and their derivatives are useful in thetreatment of atherosclerosis and hyperlipedemia through the reduction inthe expression of VCAM-1. One such derivative, AGI-1067, is described inU.S. Pat. No. 6,147,250.

Certain trans-6-[2-(3- or 4-carboxamido-substitutedpyrrol-1-yl)alkyl]-4-hydroxypyran-2-ones and the correspondingring-opened acids derived therefrom are potent inhibitors of the enzyme3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG CoA reductase) andare thus useful hypolipidemic or hypocholesterolemic agents (U.S. Pat.No. 4,681,893). Atorvastatin, a member of the statin class of HMG-CoAreductase inhibitors, is used as an oral treatment forhypercholesterolemia and dyslipidemia. It is a structural analog of thehalf-reduced intermediate of HMG-CoA and, as such, inhibits theformation of mevalonate.

Compound ML-236B (U.S. Pat. No. 3,983,140) has been isolated andpurified from the metabolic products of microorganisms of the genusPenicillium, especially Penicillium citrinum. It has been shown toinhibit the biosynthesis of cholesterol by enzymes or cultured cellsseparated from experimental animals by competing with the rate-limitingenzyme active in the biosynthesis of cholesterol, namely3-hydroxy-3-methylglutaryl-coenzyme A reductase and, as a result,significantly reduces serum cholesterol levels of animals (Journal ofAntibiotics, 29:1346 (1976)). A number of compounds structurally relatedto ML-236B also inhibit the biosynthesis of cholesterol. A series of newcompounds, which may be prepared by the enzymatic hydroxylation ofML-236B or of derivatives thereof, possess an ability to inhibit thebiosynthesis of cholesterol which is at least comparable with, and insome instances substantially exceeds, that of ML-236B itself, aredescribed in U.S. Pat. No. 4,346,227.

Humans as well as other animal organisms need insulin, a pancreatichormone, in order to utilize glucose. Insulin stimulates the movement ofthe glucose from the blood into tissue cells, especially muscular cells,and expedites the synthesis of fats as well as of proteins inpractically all organs. In diabetics, the pancreas does not produce thishormone in sufficient quantity, resulting in glucose levels in the bloodelevating, which causes the known symptoms of diabetes mellitus.

Specific sulfonylureas, which may be administered orally, possess ablood sugar reducing effect, especially in those cases were diabetesoccurs during old age (see U.S. Pat. No. 4,146,613). Compounds such asTroglitazone and Rosiglitazone can be useful for blood-glucose loweringactivity and are therefore of potential use in the treatment and/orprophylaxis of hyperglycaemia and are of particular use in the treatmentof Type II diabetes. These compounds are also useful for the treatmentand/or prophylaxis of other diseases including hyperlipidaemia,hypertension, and cardiovascular disease, especially atherosclerosis. Inaddition these compounds are considered to be useful for treatingcertain eating disorders, in particular the regulation of appetite andfood intake in subjects suffering from disorders associated withunder-eating, such as anorexia nervosa, and disorders associated withover-eating, such as obesity and anorexia bulimia (U.S. Pat. No.6,288,095)

MK-767 (U.S. Pat. No. 6,030,990) is a useful therapeutic agent for thetreatment of type-II diabetes. Type-II diabetes is a metabolic disordercharacterized by hyperglycemia as well as insulin resistance and/orimpaired insulin secretion. MK-767 is a peroxisomeproliferator-activated receptor (PPAR) alpha and gamma agonist. Thereare three isoforms of PPARs, α, β, and γ. Although they have similarinsulin-like effects, these isoforms act via different mechanisms indifferent target tissues (Calkin, A. C. et al., Current Opinions inInvestigational Drugs, 2003, 4, 4, 444). Experimental data havesuggested that drugs combining both PPARα and PPARγ activation may exerta more potent hypotriglyceridemic effect than either compound alone.

Rosiglitazone (U.S. Pat. No. 5,002,953) is a useful therapeutic agentfor the treatment of Type II diabetes. Rosiglitazone maleate is an oralantidiabetic agent, which acts primarily by increasing insulinsensitivity. Rosiglitazone improves glycemic control while reducingcirculating insulin levels. A number of side effects are associated withrosiglitazone.

Pioglitazone (U.S. Pat. Nos. 5,356,913 and 4,687,777) is a usefultherapeutic agent for the treatment of Type II diabetes.Mechanistically, pioglitazone hydrochloride decreases insulin resistancein the periphery and in the liver, resulting in increasedinsulin-dependent glucose disposal and decreased hepatic glucose output.Pioglitazone hydrochloride, like other thiazolidinediones, can causefluid retention when used alone or in combination with otherantidiabetic agents, including insulin.

R-483 (WO 02/080913) is a useful therapeutic agent for the treatment ofType II diabetes. R-483 is a potent agonist for the peroxisomeproliferator-activated receptor-gamma (PPAR-γ).

Tesaglitazar (WO 0140171 and U.S. Pat. No. 6,531,622) is a usefultherapeutic agent for the treatment of Type II diabetes. Tesaglitazar isa potent agonist for the peroxisome proliferator-activatedreceptor-gamma and alpha (PPAR-γ and PPAR-α). Activation of PPAR-γnuclear hormone receptors improves insulin sensitivity. PPAR-αactivation decreases serum triglycerides and increases serumHDL-cholestrol. Hypertriglyceridemia and low serum HDL-cholestrol arecharacteristic of both diabeticdyslipidemia and insulin resistancesyndrome. A potent activator of both PPAR-α and PPAR-γ therefore, couldpossibly replace two classes of drugs used commonly for Type IIdiabetes, namely selective PPAR-γ activator such as rosiglitazone andpioglitazone and PPAR-α-activating compounds of the fibrate group, suchas bezafibrate and fenofibrate.

Thus, there is a need for therapeutic agents for treating metabolicdisorders having improved pharmacological properties, e.g., drugs havingimproved activity for treating hypercholesterolemia, dyslipidemia,hyperlipoproteinemia, osteoporosis, atherosclerosis, hyperlipedemia,hypolipidemic, hypocholesterolemic, hyperglycaemia, type II diabetes,hypertension, cardiovascular disease, atherosclerosis, eating disorders,anorexia nervosa, obesity and/or anorexia bulimia, and pharmacokineticproperties, including improved oral bioavailability, greater potency andextended effective half-life in vivo. New compounds should have fewerside effects, less complicated dosing schedules, and be orally active.In particular, there is a need for a less onerous dosage regimen, suchas one pill, once per day.

Assay methods capable of determining the presence or absence ofmetabolic disease are of practical utility in the search for treatmentas well as for diagnosing the presence of metabolic diseases.

SUMMARY OF THE INVENTION

Intracellular targeting may be achieved by methods and compositions thatallow accumulation or retention of biologically active agents insidecells. The present invention provides novel analogs of compounds usefulto treat metabolic disorders such as hypercholesterolemia, dyslipidemia,hyperlipoproteinemia, osteoporosis, atherosclerosis, hyperlipedemia,hypolipidemic, hypocholesterolemic, hyperglycaemia, type II diabetes,hypertension, cardiovascular disease, atherosclerosis, eating disorders,anorexia nervosa, obesity and/or anorexia bulimia. Such novel analogspossess all the utilities of the parent compounds and optionally providecellular accumulation as set forth below. In addition, the presentinvention provides compositions and methods for treating metabolicdisorders or therapeutic activity against metabolic disorders.

The present invention relates generally to the accumulation or retentionof therapeutic compounds inside cells. The invention is moreparticularly related to attaining high concentrations ofphosphonate-containing molecules in target cells. Such effectivetargeting may be applicable to a variety of therapeutic formulations andprocedures. Compositions of the invention include compounds for treatingmetabolic disorders having at least one phosphonate group.

In one embodiment the invention provides a conjugate comprising acompound having activity against a metabolic disease; or apharmaceutically acceptable salt or solvate thereof.

In another embodiment the invention provides a conjugate, or apharmaceutically acceptable salt or solvate thereof, that is a compoundof any one of formulae 500-523:

substituted with one or more groups A⁰;wherein:

A⁰ is A¹, A² or W³ with the proviso that the conjugate includes at leastone A¹;

A¹ is:

A² is:

A³ is:

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N((R^(x))(R^(x)));

Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—;and when Y² joins two phosphorous atoms Y² can also be C(R²)(R²);

R^(x) is independently H, R¹, R², W³, a protecting group, or theformula:

wherein:

R^(y) is independently H, W³, R² or a protecting group;

R¹ is independently H or alkyl of 1 to 18 carbon atoms;

R² is independently H, R¹, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups or taken together at a carbon atom,two R² groups form a ring of 3 to 8 carbons and the ring may besubstituted with 0 to 3 R³ groups;

R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is boundto a heteroatom, then R³ is R^(3c) or R^(3d);

R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;

R^(3b) is Y¹;

R^(3c) is —R^(x), N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x), —S(O)₂R^(x),—S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x), —OC(Y¹)OR^(x),—OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x)));

R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

W³ is W⁴ or W⁵;

W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO_(M2)R⁵, or —SO_(M2)W⁵;

W⁵ is carbocycle or heterocycle wherein W⁵ is independently substitutedwith 0 to 3 R² groups;

W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;

M2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M1a, M1c, and M1d are independently 0 or 1; and

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

In another embodiment, the invention also provides a conjugate, or apharmaceutically acceptable salt or solvate thereof, which has theformula:

[DRUG]-(A⁰)_(nn)

wherein:

DRUG is a compound of any one of formulae 500-523;

nn is 1, 2, or 3;

A⁰ is A¹, A² or W³ with the proviso that the conjugate includes at leastone A¹;

A¹ is:

A² is:

A³ is:

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x)));

Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—;and when Y² joins two phosphorous atoms Y² can also be C(R²)(R²);

R^(x) is independently H, R¹, R², W³, a protecting group, or theformula:

wherein:

R^(y) is independently H, W³, R² or a protecting group;

R¹ is independently H or alkyl of 1 to 18 carbon atoms;

R² is independently H, R¹, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups or taken together at a carbon atom,two R² groups form a ring of 3 to 8 carbons and the ring may besubstituted with 0 to 3 R³ groups;

R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is boundto a heteroatom, then R³ is R^(3c) or R^(3d);

R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;

R^(3b) is Y;

R^(3c) is R^(x), N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x), —S(O)₂R^(x),—S(O)(OR^(x)), S(O)₂(OR^(x)), —OC(Y¹)R^(x), —OC(Y¹)OR^(x),—OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), —N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x)));

R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

W³ is W⁴ or W;

W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO_(M2)R⁵, or —SO_(M2)W⁵;

W⁵ is carbocycle or heterocycle wherein W⁵ is independently substitutedwith 0 to 3 R² groups;

W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;

M2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M1a, M1c, and M1d are independently 0 or 1; and

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

In another embodiment, the invention also provides a conjugate which hasany one of formulae I-51:

wherein:

A⁰ is A¹;

A¹ is:

A³ is:

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x)));

Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(O)(OR^(x)),N(N(R^(x))(R^(x))), —S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—; and when Y²joins two phosphorous atoms Y² can also be C(R²)(R²);

R^(x) is independently H, R², W³, a protecting group, or the formula:

R^(y) is independently H, W³, R² or a protecting group;

R¹ is independently H or alkyl of 1 to 18 carbon atoms;

R² is independently H, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups;

R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is boundto a heteroatom, then R³ is R^(3c) or R^(3d);

R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;

R^(3b) is Y¹;

R^(3c) is —R^(x), —N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x), —S(O)₂R^(x),—S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x), —OC(Y¹)OR^(x),—OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), —N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x)));

R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

R^(5a) is independently alkylene of 1 to 18 carbon atoms, alkenylene of2 to 18 carbon atoms, or alkynylene of 2-18 carbon atoms any one ofwhich alkylene, alkenylene or alkynylene is substituted with 0-3 R³groups;

W³ is W⁴ or W⁵;

W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO₂R⁵, or —SO₂W⁵;

W⁵ is carbocycle or heterocycle wherein W⁵ is independently substitutedwith 0 to 3 R² groups;

W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;

M2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M1a, M1c, and M1d are independently 0 or 1;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

X⁵¹ and X⁵² are the same or different and each represents hydrogen orC₁-C₅ alkyl;

X⁵³ and X⁵⁴ are the same or different and each represents hydrogen, aC₁-C₅ alkyl group or a C₁-C₅ alkoxy group, or X⁵³ and X⁵⁴ togetherrepresent a C₁-C₄ alkylenedioxy group;

X⁵⁶ represents a —CH₂—, >CO or >CH—OX⁵⁵ group;

X⁵⁵ represents hydrogen; C₁-C₆ aliphatic acyl; (C₅-C₇cycloalkane)carbonyl; benzoyl, benzoyl substituted with one to threesubstituents selected from the group of C₁-C₄ alkyl, C₁-C₄ alkoxy,hydroxy, halogen, nitro, amino and di(C₁-C₄ alkyl)amino; naphthoyl; 4-7membered heterocyclic acyl wherein heterocyclic moiety has O, S or Nhetero atoms; phenyl(C₂-C₃)aliphatic acyl; cinnamoyl; (C₁-C₆alkoxy)carbonyl; or benzoyloxycarbonyl;

X⁵⁷ represents a hydrogen atom, an alkyl group, an acyl group, anaralkyl group, wherein the aryl moiety may be substituted orunsubstituted, or a substituted or unsubstituted aryl group;

X⁵⁸ represents hydrogen or 1 to 4 optional substituents selected fromthe group consisting of alkyl, alkoxy, aryl and halogen or X⁵⁸represents two substituents on adjacent carbon atoms, which substituentstogether with the carbon atoms to which they are attached form asubstituted or unsubstituted aryl group;

X⁵⁹ represents O, NX⁶⁰, CH₂O, CH₂NX⁶⁰;

X⁶⁰ represents H or lower alkyl with one or two carbons;

X⁶¹ is selected from 5 or 6 membered aromatic ring with zero, one, ortwo heteroatoms with substituents. The substituents of the aromatic ringcan be hydrogen, halogen, alkyl and alkoxy of one to six carbon atoms,hydroxy, amino, acetylamino and phenyl, wherein the alkyl, alkoxy andphenyl radicals may be substituted by at least one member selected fromthe group consisting of halogen, lower alkyl and lower alkoxy;

X⁶² is selected from the group consisting of lower alkyl of one to fourcarbon atoms, lower alkenyl of one to four carbon atoms, cycloaliphaticand substituted cycloaliphatic, preferably cycloalkyl and substitutedcycloalkyl wherein the cyclic ring contains five to eight carbon atomspreferably five to six carbon atoms, and may be substituted by loweralkyl or lower alkoxy;

X⁶³, X⁶⁴, and X⁶⁵ are independently selected from the group consistingof hydrogen, halogen, alkyl and alkoxy of one to six carbon atoms,hydroxy, amino, acetylamino and phenyl, wherein the alkyl, alkoxy andphenyl radicals may be substituted by at least one member selected fromthe group consisting of halogen, lower alkyl and lower alkoxy;

X⁶⁶ is selected from the group consisting of O, N X⁶⁷, CH₂O, CH₂N X⁶⁷;

X⁶⁷ is selected from H or lower alkyl with one or two carbons; and

X⁶⁸ is selected from alkylene or alkenylene having from 3 to 6 carbonatoms, optionally substituted by up to 3 alkyl groups each having from 1to 4 carbon atoms, or a phenyl radical; or cycloalkylenealkyl having upto 3 carbon atoms in the alkyl moiety and from 5 to 7 ring carbon atoms,optionally substituted by up to 3 methyl groups.

The invention also provides a pharmaceutical composition comprising aneffective amount of a compound of the invention, or a pharmaceuticallyacceptable salt or solvate thereof, in combination with apharmaceutically acceptable diluent or carrier.

This invention pertains to a method of increasing cellular accumulationand retention of drug compounds, thus improving their therapeutic anddiagnostic value.

The invention also provides a method of treating metabolic disorderscomprising administering to a mammal afflicted with a metabolicdisorder, an amount of a compound of the invention, or apharmaceutically acceptable salt or solvate thereof, effective to treata metabolic disorder, e.g., to inhibit cholesterol synthesis.

The invention also provides a compound of the invention or apharmaceutically acceptable salt or solvate thereof, for use in medicaltherapy (preferably for use in treating a metabolic disorder), as wellas the use of a compound of the invention for the manufacture of amedicament useful for the treatment of a metabolic disorder.

The invention also provides processes and novel intermediates disclosedherein which are useful for preparing compounds of the invention. Someof the compounds of the invention are useful to prepare other compoundsof the invention.

In another aspect of the invention, a metabolic disease is inhibited bya method comprising the step of treating a sample suspected of having ametabolic disease with a compound or composition of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to certain claims of the invention,examples of which are illustrated in the accompanying structures andformulas. While the invention will be described in conjunction with theenumerated claims, it will be understood that they are not intended tolimit the invention to those claims. On the contrary, the invention isintended to cover all alternatives, modifications, and equivalents,which may be included within the scope of the present invention asdefined by the claims.

DEFINITIONS

Unless stated otherwise, the following terms and phrases as used hereinare intended to have the following meanings:

When tradenames are used herein, applicants intend to independentlyinclude the tradename product and the active pharmaceuticalingredient(s) of the tradename product.

“Bioavailability” is the degree to which the pharmaceutically activeagent becomes available to the target tissue after the agent'sintroduction into the body. Enhancement of the bioavailability of apharmaceutically active agent can provide a more efficient and effectivetreatment for patients because, for a given dose, more of thepharmaceutically active agent will be available at the targeted tissuesites.

The terms “phosphonate” and “phosphonate group” include functionalgroups or moieties within a molecule that comprises a phosphorous thatis 1) single-bonded to a carbon, 2) double-bonded to a heteroatom, 3)single-bonded to a heteroatom, and 4) single-bonded to anotherheteroatom, wherein each heteroatom can be the same or different. Theterms “phosphonate” and “phosphonate group” also include functionalgroups or moieties that comprise a phosphorous in the same oxidationstate as the phosphorous described above, as well as functional groupsor moieties that comprise a prodrug moiety that can separate from acompound so that the compound retains a phosphorous having thecharacteristics described above. For example, the terms “phosphonate”and “phosphonate group” include phosphonic acid, phosphonic monoester,phosphonic diester, phosphonamidate, and phosphonthioate functionalgroups. In one specific embodiment of the invention, the terms“phosphonate” and “phosphonate group” include functional groups ormoieties within a molecule that comprises a phosphorous that is 1)single-bonded to a carbon, 2) double-bonded to an oxygen, 3)single-bonded to an oxygen, and 4) single-bonded to another oxygen, aswell as functional groups or moieties that comprise a prodrug moietythat can separate from a compound so that the compound retains aphosphorous having such characteristics. In another specific embodimentof the invention, the terms “phosphonate” and “phosphonate group”include functional groups or moieties within a molecule that comprises aphosphorous that is 1) single-bonded to a carbon, 2) double-bonded to anoxygen, 3) single-bonded to an oxygen or nitrogen, and 4) single-bondedto another oxygen or nitrogen, as well as functional groups or moietiesthat comprise a prodrug moiety that can separate from a compound so thatthe compound retains a phosphorous having such characteristics.

The term “prodrug” as used herein refers to any compound that whenadministered to a biological system generates the drug substance, i.e.active ingredient, as a result of spontaneous chemical reaction(s),enzyme catalyzed chemical reaction(s), photolysis, and/or metabolicchemical reaction(s). A prodrug is thus a covalently modified analog orlatent form of a therapeutically-active compound.

“Prodrug moiety” refers to a labile functional group which separatesfrom the active inhibitory compound during metabolism, systemically,inside a cell, by hydrolysis, enzymatic cleavage, or by some otherprocess (Bundgaard, Hans, “Design and Application of Prodrugs” in ATextbook of Drug Design and Development (1991), P. Krogsgaard-Larsen andH. Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191). Enzymeswhich are capable of an enzymatic activation mechanism with thephosphonate prodrug compounds of the invention include, but are notlimited to, amidases, esterases, microbial enzymes, phospholipases,cholinesterases, and phosphases. Prodrug moieties can serve to enhancesolubility, absorption and lipophilicity to optimize drug delivery,bioavailability and efficacy. A prodrug moiety may include an activemetabolite or drug itself.

Exemplary prodrug moieties include the hydrolytically sensitive orlabile acyloxymethyl esters —CH₂C(═O)R⁹ and acyloxymethyl carbonates—CH₂C(═O)OR⁹ where R⁹ is C₁-C₆ alkyl, C₁-C₆ substituted alkyl, C₆-C₂₀aryl or C₆-C₂₀ substituted aryl. The acyloxyalkyl ester was first usedas a prodrug strategy for carboxylic acids and then applied tophosphates and phosphonates by Farquhar et al. (1983) J. Pharm. Sci. 72:324; also U.S. Pat. Nos. 4,816,570, 4,968,788, 5,663,159 and 5,792,756.Subsequently, the acyloxyalkyl ester was used to deliver phosphonicacids across cell membranes and to enhance oral bioavailability. A closevariant of the acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester(carbonate), may also enhance oral bioavailability as a prodrug moietyin the compounds of the combinations of the invention. An exemplaryacyloxymethyl ester is pivaloyloxymethoxy, (POM) —CH₂C(═O)C(CH₃)₃. Anexemplary acyloxymethyl carbonate prodrug moiety ispivaloyloxymethylcarbonate (POC)—CH₂C(═O)OC(CH₃)₃.

The phosphonate group may be a phosphonate prodrug moiety. The prodrugmoiety may be sensitive to hydrolysis, such as, but not limited to apivaloyloxymethyl carbonate (POC) or POM group. Alternatively, theprodrug moiety may be sensitive to enzymatic potentiated cleavage, suchas a lactate ester or a phosphonamidate-ester group.

Aryl esters of phosphorus groups, especially phenyl esters, are reportedto enhance oral bioavailability (De Lombaert et al. (1994) J. Med. Chem.37: 498). Phenyl esters containing a carboxylic ester ortho to thephosphate have also been described (Khammei and Torrence, (1996) J. Med.Chem. 39:4109-4115). Benzyl esters are reported to generate the parentphosphonic acid. In some cases, substituents at the ortho- orpara-position may accelerate the hydrolysis. Benzyl analogs with anacylated phenol or an alkylated phenol may generate the phenoliccompound through the action of enzymes, e.g., esterases, oxidases, etc.,which in turn undergoes cleavage at the benzylic C—O bond to generatethe phosphoric acid and the quinone methide intermediate. Examples ofthis class of prodrugs are described by Mitchell et al. (1992) J. Chem.Soc. Perkin Trans. II 2345; Glazier WO 91/19721. Still other benzylicprodrugs have been described containing a carboxylic ester-containinggroup attached to the benzylic methylene (Glazier WO 91/19721).Thio-containing prodrugs are reported to be useful for the intracellulardelivery of phosphonate drugs. These proesters contain an ethylthiogroup in which the thiol group is either esterified with an acyl groupor combined with another thiol group to form a disulfide.Deesterification or reduction of the disulfide generates the free thiointermediate which subsequently breaks down to the phosphoric acid andepisulfide (Puech et al. (1993) Antiviral Res., 22: 155-174; Benzaria etal. (1996) J. Med. Chem. 39: 4958). Cyclic phosphonate esters have alsobeen described as prodrugs of phosphorus-containing compounds (Erion etal., U.S. Pat. No. 6,312,662).

“Protecting group” refers to a moiety of a compound that masks or altersthe properties of a functional group or the properties of the compoundas a whole. Chemical protecting groups and strategies forprotection/deprotection are well known in the art. See e.g., ProtectiveGroups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons,Inc., New York, 1991. Protecting groups are often utilized to mask thereactivity of certain functional groups, to assist in the efficiency ofdesired chemical reactions, e.g., making and breaking chemical bonds inan ordered and planned fashion. Protection of functional groups of acompound alters other physical properties besides the reactivity of theprotected functional group, such as the polarity, lipophilicity(hydrophobicity), and other properties which can be measured by commonanalytical tools. Chemically protected intermediates may themselves bebiologically active or inactive.

Protected compounds may also exhibit altered, and in some cases,optimized properties in vitro and in vivo, such as passage throughcellular membranes and resistance to enzymatic degradation orsequestration. In this role, protected compounds with intendedtherapeutic effects may be referred to as prodrugs. Another function ofa protecting group is to convert the parental drug into a prodrug,whereby the parental drug is released upon conversion of the prodrug invivo. Because active prodrugs may be absorbed more effectively than theparental drug, prodrugs may possess greater potency in vivo than theparental drug. Protecting groups are removed either in vitro, in theinstance of chemical intermediates, or in vivo, in the case of prodrugs.With chemical intermediates, it is not particularly important that theresulting products after deprotection, e.g., alcohols, bephysiologically acceptable, although in general it is more desirable ifthe products are pharmacologically innocuous.

Any reference to any of the compounds of the invention also includes areference to a physiologically acceptable salt thereof. Examples ofphysiologically acceptable salts of the compounds of the inventioninclude salts derived from an appropriate base, such as an alkali metal(for example, sodium), an alkaline earth (for example, magnesium),ammonium and NX₄ ⁺ (wherein X is C₁-C₄ alkyl). Physiologicallyacceptable salts of an hydrogen atom or an amino group include salts oforganic carboxylic acids such as acetic, benzoic, lactic, fumaric,tartaric, maleic, malonic, malic, isethionic, lactobionic and succinicacids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic,benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, suchas hydrochloric, sulfuric, phosphoric and sulfamic acids.Physiologically acceptable salts of a compound of an hydroxy groupinclude the anion of said compound in combination with a suitable cationsuch as Na⁺ and NX₄ ⁺ (wherein X is independently selected from H or aC₁-C₄ alkyl group).

For therapeutic use, salts of active ingredients of the compounds of theinvention will be physiologically acceptable, i.e. they will be saltsderived from a physiologically acceptable acid or base. However, saltsof acids or bases which are not physiologically acceptable may also finduse, for example, in the preparation or purification of aphysiologically acceptable compound. All salts, whether or not derivedform a physiologically acceptable acid or base, are within the scope ofthe present invention.

“Alkyl” is C₁-C₁₈ hydrocarbon containing normal, secondary, tertiary orcyclic carbon atoms. Examples are methyl (Me, —CH₃), ethyl (Et,—CH₂CH₃), 1-propyl (n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr,i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃),2-methyl-1-propyl (i-Bu, i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl,—CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl(n-pentyl, —CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃.

“Alkenyl” is C₂-C₁₈ hydrocarbon containing normal, secondary, tertiaryor cyclic carbon atoms with at least one site of unsaturation, i.e. acarbon-carbon, sp² double bond. Examples include, but are not limitedto, ethylene or vinyl (—CH═CH₂), allyl (—CH₂CH═CH₂), cyclopentenyl(—C₅H₇), and 5-hexenyl (—CH₂ CH₂CH₂CH₂CH═CH₂).

“Alkynyl” is C₂-C₁₈ hydrocarbon containing normal, secondary, tertiaryor cyclic carbon atoms with at least one site of unsaturation, i.e. acarbon-carbon, sp triple bond. Examples include, but are not limited to,acetylenic (—C≡CH) and propargyl (—CH₂C≡CH).

“Alkylene” refers to a saturated, branched or straight chain or cyclichydrocarbon radical of 1-18 carbon atoms, and having two monovalentradical centers derived by the removal of two hydrogen atoms from thesame or two different carbon atoms of a parent alkane. Typical alkyleneradicals include, but are not limited to, methylene (—CH₂—) 1,2-ethyl(—CH₂CH₂—), 1,3-propyl (—CH₂CH₂CH₂—), 1,4-butyl (—CH₂CH₂CH₂CH₂—), andthe like.

“Alkenylene” refers to an unsaturated, branched or straight chain orcyclic hydrocarbon radical of 2-18 carbon atoms, and having twomonovalent radical centers derived by the removal of two hydrogen atomsfrom the same or two different carbon atoms of a parent alkene. Typicalalkenylene radicals include, but are not limited to, 1,2-ethylene(—CH═CH—).

“Alkynylene” refers to an unsaturated, branched or straight chain orcyclic hydrocarbon radical of 2-18 carbon atoms, and having twomonovalent radical centers derived by the removal of two hydrogen atomsfrom the same or two different carbon atoms of a parent alkyne. Typicalalkynylene radicals include, but are not limited to, acetylene (—C≡C—),propargyl (—CH₂C≡C—), and 4-pentynyl (—CH₂CH₂CH₂C≡CH—).

“Aryl” means a monovalent aromatic hydrocarbon radical of 6-20 carbonatoms derived by the removal of one hydrogen atom from a single carbonatom of a parent aromatic ring system. Typical aryl groups include, butare not limited to, radicals derived from benzene, substituted benzene,naphthalene, anthracene, biphenyl, and the like.

“Arylalkyl” refers to an acyclic alkyl radical in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, is replaced with an aryl radical. Typical arylalkyl groupsinclude, but are not limited to, benzyl, 2-phenylethan-1-yl,naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl,2-naphthophenylethan-1-yl and the like. The arylalkyl group comprises 6to 20 carbon atoms, e.g., the alkyl moiety, including alkanyl, alkenylor alkynyl groups, of the arylalkyl group is 1 to 6 carbon atoms and thearyl moiety is 5 to 14 carbon atoms.

“Substituted alkyl”, “substituted aryl”, and “substituted arylalkyl”mean alkyl, aryl, and arylalkyl respectively, in which one or morehydrogen atoms are each independently replaced with a non-hydrogensubstituent. Typical substituents include, but are not limited to, —X,—R, —O⁻, —OR, —SR, —S—, —NR₂, —NR₃, ═NR, —CX₃, —CN, —OCN, —SCN, —N═C═O,—NCS, —NO, —NO₂, ═N₂, —N₃, NC(═O)R, —C(═O)R, —C(═O)NRR—S(═O)₂O⁻,—S(═O)₂OH, —S(O)₂R, —OS(═O)₂OR, —S(═O)₂NR, —S(═O)R, —OP(═O)O₂RR,—P(═O)O₂RR—P(═O)(O—)₂, —P(═O)(OH)₂, —C(═O)R, —C(═O)X, —C(S)R, —C(O)OR,—C(O)O⁻, —C(S)OR, —C(O)SR, —C(S)SR, —C(O)NRR, —C(S)NRR, —C(NR)NRR, whereeach X is independently a halogen: F, Cl, Br, or I; and each R isindependently —H, alkyl, aryl, heterocycle, protecting group or prodrugmoiety. Alkylene, alkenylene, and alkynylene groups may also besimilarly substituted.

“Heterocycle” as used herein includes by way of example and notlimitation these heterocycles described in Paquette, Leo A.; Principlesof Modern Heterocyclic Chemistry (W. A. Benjamin, New York, 1968),particularly Chapters 1, 3, 4, 6, 7, and 9; The Chemistry ofHeterocyclic Compounds, A Series of Monographs” (John Wiley & Sons, NewYork, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28;and J. Am. Chem. Soc. (1960) 82:5566. In one specific embodiment of theinvention “heterocycle” includes a “carbocycle” as defined herein,wherein one or more (e.g. 1, 2, 3, or 4) carbon atoms have been replacedwith a heteroatom (e.g. O, N, or S).

Examples of heterocycles include by way of example and not limitationpyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl,tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl,furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl,benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl,isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl,2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl,azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl,thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl,phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl,pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl,4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl,chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl,piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl,oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl,isatinoyl, and bis-tetrahydrofuranyl:

By way of example and not limitation, carbon bonded heterocycles arebonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2,3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan,tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole,position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4,or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of anaziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6,7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of anisoquinoline. Still more typically, carbon bonded heterocycles include2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl,5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

By way of example and not limitation, nitrogen bonded heterocycles arebonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine,2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline,3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline,piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of aisoindole, or isoindoline, position 4 of a morpholine, and position 9 ofa carbazole, or β-carboline. Still more typically, nitrogen bondedheterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl,1-pyrazolyl, and 1-piperidinyl.

“Carbocycle” refers to a saturated, unsaturated or aromatic ring having3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle,and up to about 20 carbon atoms as a polycycle. Monocyclic carbocycleshave 3 to 6 ring atoms, still more typically 5 or 6 ring atoms. Bicycliccarbocycles have 7 to 12 ring atoms, e.g., arranged as a bicyclo [4,5],[5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as abicyclo [5,6] or [6,6] system. Examples of monocyclic carbocyclesinclude cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl,1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl,1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl, spiryl and naphthyl.

“Linker” or “link” refers to a chemical moiety comprising a covalentbond or a chain or group of atoms that covalently attaches a phosphonategroup to a drug. Linkers include portions of substituents A¹ and A³,which include moieties such as: repeating units of alkyloxy (e.g.,polyethylenoxy, PEG, polymethyleneoxy) and alkylamino (e.g.,polyethyleneamino, Jeffamine™); and diacid ester and amides includingsuccinate, succinamide, diglycolate, malonate, and caproamide.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement of theatoms or groups in space.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g., melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers may separate under high resolution analytical proceduressuch as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

The term “treatment” or “treating,” to the extent it relates to adisease or condition includes preventing the disease or condition fromoccurring, inhibiting the disease or condition, eliminating the diseaseor condition, and/or relieving one or more symptoms of the disease orcondition.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., NewYork. Many organic compounds exist in optically active forms, i.e., theyhave the ability to rotate the plane of plane-polarized light. Indescribing an optically active compound, the prefixes D and L or R and Sare used to denote the absolute configuration of the molecule about itschiral center(s). The prefixes d and l or (+) and (−) are employed todesignate the sign of rotation of plane-polarized light by the compound,with (−) or 1 meaning that the compound is levorotatory. A compoundprefixed with (+) or d is dextrorotatory. For a given chemicalstructure, these stereoisomers are identical except that they are mirrorimages of one another. A specific stereoisomer may also be referred toas an enantiomer, and a mixture of such isomers is often called anenantiomeric mixture. A 50:50 mixture of enantiomers is referred to as aracemic mixture or a racemate, which may occur where there has been nostereoselection or stereospecificity in a chemical reaction or process.The terms “racemic mixture” and “racemate” refer to an equimolar mixtureof two enantiomeric species, devoid of optical activity.

Protecting Groups

In the context of the present invention, protecting groups includeprodrug moieties and chemical protecting groups.

Protecting groups are available, commonly known and used, and areoptionally used to prevent side reactions with the protected groupduring synthetic procedures, i.e. routes or methods to prepare thecompounds of the invention. For the most part the decision as to whichgroups to protect, when to do so, and the nature of the chemicalprotecting group “PG” will be dependent upon the chemistry of thereaction to be protected against (e.g., acidic, basic, oxidative,reductive or other conditions) and the intended direction of thesynthesis. The PG groups do not need to be, and generally are not, thesame if the compound is substituted with multiple PG. In general, PGwill be used to protect functional groups such as carboxyl, hydroxyl,thio, or amino groups and to thus prevent side reactions or to otherwisefacilitate the synthetic efficiency. The order of deprotection to yieldfree, deprotected groups is dependent upon the intended direction of thesynthesis and the reaction conditions to be encountered, and may occurin any order as determined by the artisan.

Various functional groups of the compounds of the invention may beprotected. For example, protecting groups for —OH groups (whetherhydroxyl, carboxylic acid, phosphonic acid, or other functions) areclaims of “ether- or ester-forming groups.” Ether- or ester-forminggroups are capable of functioning as chemical protecting groups in thesynthetic schemes set forth herein. However, some hydroxyl and thioprotecting groups are neither ether-nor ester-forming groups, as will beunderstood by those skilled in the art, and are included with amides,discussed below.

A very large number of hydroxyl protecting groups and amide-forminggroups and corresponding chemical cleavage reactions are described inProtective Groups in Organic Synthesis, Theodora W. Greene (John Wiley &Sons, Inc., New York, 1991, ISBN 0-471-62301-6) (“Greene”). See alsoKocienski, Philip J.; Protecting Groups (Georg Thieme Verlag Stuttgart,N.Y., 1994), which is incorporated by reference in its entirety herein.In particular Chapter 1, Protecting Groups: An Overview, pages 1-20,Chapter 2, Hydroxyl Protecting Groups, pages 21-94, Chapter 3, DiolProtecting Groups, pages 95-117, Chapter 4, Carboxyl Protecting Groups,pages 118-154, Chapter 5, Carbonyl Protecting Groups, pages 155-184. Forprotecting groups for carboxylic acid, phosphonic acid, phosphonate,sulfonic acid and other protecting groups for acids see Greene as setforth below. Such groups include by way of example and not limitation,esters, amides, hydrazides, and the like.

Ether- and Ester-Forming Protecting Groups

Ester-forming groups include: (1) phosphonate ester-forming groups, suchas phosphonamidate esters, phosphorothioate esters, phosphonate esters,and phosphon-bis-amidates; (2) carboxyl ester-forming groups, and (3)sulphur ester-forming groups, such as sulphonate, sulfate, andsulfinate.

The phosphonate moieties of the compounds of the invention may or maynot be prodrug moieties, i.e. they may or may be susceptible tohydrolytic or enzymatic cleavage or modification. Certain phosphonatemoieties are stable under most or nearly all metabolic conditions. Forexample, a dialkylphosphonate, where the alkyl groups are two or morecarbons, may have appreciable stability in vivo due to a slow rate ofhydrolysis.

Within the context of phosphonate prodrug moieties, a large number ofstructurally-diverse prodrugs have been described for phosphonic acids(Freeman and Ross in Progress in Medicinal Chemistry 34: 112-147 (1997)and are included within the scope of the present invention. An exemplaryphosphonate ester-forming group is the phenyl carbocycle in substructureA₃ having the formula:

wherein R₁ may be H or C₁-C₁₂ alkyl; m1 is 1, 2, 3, 4, 5, 6, 7 or 8, andthe phenyl carbocycle is substituted with 0 to 3 R₂ groups. Where Y₁ isO, a lactate ester is formed, and where Y₁ is N(R₂), N(OR₂) or N(N(R₂)₂,a phosphonamidate ester results.

In its ester-forming role, a protecting group typically is bound to anyacidic group such as, by way of example and not limitation, a —CO₂H or—C(S)OH group, thereby resulting in —CO₂R^(x) where R^(x) is definedherein. Also, R^(x) for example includes the enumerated ester groups ofWO 95/07920.

Examples of protecting groups include:

C₃-C₁₂ heterocycle (described above) or aryl. These aromatic groupsoptionally are polycyclic or monocyclic. Examples include phenyl,spiryl, 2- and 3-pyrrolyl, 2- and 3-thienyl, 2- and 4-imidazolyl, 2-, 4-and 5-oxazolyl, 3- and 4-isoxazolyl, 2-, 4- and 5-thiazolyl, 3-, 4- and5-isothiazolyl, 3- and 4-pyrazolyl, 1-, 2-, 3- and 4-pyridinyl, and 1-,2-, 4- and 5-pyrimidinyl,

C₃-C₁₂ heterocycle or aryl substituted with halo, R¹, R¹—O—C₁-C₁₂alkylene, C₁-C₁₂ alkoxy, CN, NO₂, OH, carboxy, carboxyester, thiol,thioester, C₁-C₁₂ haloalkyl (1-6 halogen atoms), C₂-C₁₂ alkenyl orC₂-C₁₂ alkynyl. Such groups include 2-, 3- and 4-alkoxyphenyl (C₁-C₁₂alkyl), 2-, 3- and 4-methoxyphenyl, 2-, 3- and 4-ethoxyphenyl, 2,3-,2,4-, 2,5-, 2,6-, 3,4- and 3,5-diethoxyphenyl, 2- and3-carboethoxy-4-hydroxyphenyl, 2- and 3-ethoxy-4-hydroxyphenyl, 2- and3-ethoxy-5-hydroxyphenyl, 2- and 3-ethoxy-6-hydroxyphenyl, 2-, 3- and4-O-acetylphenyl, 2-, 3- and 4-dimethylaminophenyl, 2-, 3- and4-methylmercaptophenyl, 2-, 3- and 4-halophenyl (including 2-, 3- and4-fluorophenyl and 2-, 3- and 4-chlorophenyl), 2,3-, 2,4-, 2,5-, 2,6-,3,4- and 3,5-dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and3,5-biscarboxyethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and3,5-dimethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dihalophenyl(including 2,4-difluorophenyl and 3,5-difluorophenyl), 2-, 3- and4-haloalkylphenyl (1 to 5 halogen atoms, C₁-C₁₂ alkyl including4-trifluoromethylphenyl), 2-, 3- and 4-cyanophenyl, 2-, 3- and4-nitrophenyl, 2-, 3- and 4-haloalkylbenzyl (1 to 5 halogen atoms,C₁-C₁₂ alkyl including 4-trifluoromethylbenzyl and 2-, 3- and4-trichloromethylphenyl and 2-, 3- and 4-trichloromethylphenyl),4-N-methylpiperidinyl, 3-N-methylpiperidinyl, 1-ethylpiperazinyl,benzyl, alkylsalicylphenyl (C₁-C₄ alkyl, including 2-, 3- and4-ethylsalicylphenyl), 2-, 3- and 4-acetylphenyl, 1,8-dihydroxynaphthyl(—C₁₀H₆—OH) and aryloxy ethyl [C₆-C₈ aryl (including phenoxy ethyl)],2,2′-dihydroxybiphenyl, 2-, 3- and 4-N,N-dialkylaminophenol,—C₆H₄—CH₂—N(CH₃)₂, trimethoxybenzyl, triethoxybenzyl, 2-alkyl pyridinyl(C₁₋₄ alkyl);

C₄-C₈ esters of 2-carboxyphenyl; and C₁-C₄ alkylene-C₃-C₆ aryl(including benzyl, —CH₂-pyrrolyl, —CH₂-thienyl, —CH₂-imidazolyl,—CH₂-oxazolyl, —CH₂-isoxazolyl, —CH₂-thiazolyl, —CH₂-isothiazolyl,—CH₂-pyrazolyl, —CH₂-pyridinyl and —CH₂-pyrimidinyl) substituted in thearyl moiety by 3 to 5 halogen atoms or 1 to 2 atoms or groups selectedfrom halogen, C₁-C₁₂ alkoxy (including methoxy and ethoxy), cyano,nitro, OH, C₁-C₁₂ haloalkyl (1 to 6 halogen atoms; including —CH₂CCl₃),C₁-C₁₂ alkyl (including methyl and ethyl), C₂-C₁₂ alkenyl or C₂-C₁₂alkynyl; alkoxy ethyl [C₁-C₆ alkyl including —CH₂—CH₂—O—CH₃ (methoxyethyl)]; alkyl substituted by any of the groups set forth above foraryl, in particular OH or by 1 to 3 halo atoms (including —CH₃,—CH(CH₃)₂, —C(CH₃)₃, —CH₂CH₃, —(CH₂)₂CH₃, —(CH₂)₃CH₃, —(CH₂)₄—CH₃,—(CH₂)₅CH₃, —CH₂CH₂F, —CH₂CH₂Cl, —CH₂CF₃, and —CH₂CCl₃);

—N-2-propylmorpholino, 2,3-dihydro-6-hydroxyindene, sesamol, catecholmonoester, —CH₂—C(O)—N(R¹)₂, —CH₂—S(O)(R¹), —CH₂—S(O)₂(R¹),—CH₂—CH(OC(O)CH₂R¹)—CH₂(OC(O)CH₂R¹), cholesteryl, enolpyruvate(HOOC—C(═CH₂)—), glycerol;

a 5 or 6 carbon monosaccharide, disaccharide or oligosaccharide (3 to 9monosaccharide residues);

triglycerides such as α-D-β-diglycerides (wherein the fatty acidscomposing glyceride lipids generally are naturally occurring saturatedor unsaturated C₆₋₂₆, C₆₋₁₈ or C₆₋₁₀ fatty acids such as linoleic,lauric, myristic, palmitic, stearic, oleic, palmitoleic, linolenic andthe like fatty acids) linked to acyl of the parental compounds hereinthrough a glyceryl oxygen of the triglyceride;

phospholipids linked to the carboxyl group through the phosphate of thephospho lipid;

phthalidyl (shown in FIG. 1 of Clayton et al., Antimicrob. Agents Chemo.(1974) 5(6):670-671);

cyclic carbonates such as (5-R_(d)-2-oxo-1,3-dioxolen-4-yl)methyl esters(Sakamoto et al., Chem. Pharm. Bull. (1984) 32(6)2241-2248) where R_(d)is R₁, R₄ or aryl; and

The hydroxyl groups of the compounds of this invention optionally aresubstituted with one of groups III, IV or V disclosed in WO 94/21604, orwith isopropyl.

Table A lists examples of protecting group ester moieties that forexample can be bonded via oxygen to —C(O)O— and —P(O)(O—)₂ groups.Several amidates also are shown, which are bound directly to —C(O)— or—P(O)₂. Esters of structures 1-5, 8-10 and 16, 17, 19-22 are synthesizedby reacting the compound herein having a free hydroxyl with thecorresponding halide (chloride or acyl chloride and the like) andN,N-dicyclohexyl-N-morpholine carboxamidine (or another base such asDBU, triethylamine, CsCO₃, N,N-dimethylaniline and the like) in DMF (orother solvent such as acetonitrile or N-methylpyrrolidone). When thecompound to be protected is a phosphonate, the esters of structures 5-7,11, 12, 21, and 23-26 are synthesized by reaction of the alcohol oralkoxide salt (or the corresponding amines in the case of compounds suchas 13, 14 and 15) with the monochlorophosphonate or dichlorophosphonate(or another activated phosphonate).

TABLE A  1. —CH₂—C(O)—N(R₁)₂*  2. —CH₂—S(O)(R₁)  3. —CH₂—S(O)₂(R₁)  4.—CH₂—O—C(O)-CH₂—C₆H₅  5. 3-cholesteryl  6. 3-pyridyl  7.N-ethylmorpholino  8. —CH₂—O—C(O)—C₆H₅  9. —CH₂—O—C(O)—CH₂CH₃ 10.—CH₂—O—C(O)—C(CH₃)₃ 11. —CH₂—CCl₃ 12. —C₆H₅ 13. —NH—CH₂—C(O)O—CH₂CH₃ 14.—N(CH₃)—CH₂—C(O)O—CH₂CH₃ 15. —NHR₁ 16. —CH₂—O—C(O)—C₁₀H₁₅ 17.—CH₂—O—C(O)—CH(CH₃)₂ 18. —CH₂—C#H(OC(O)CH₂R₁)—CH₂— —(OC(O)CH₂R₁)* 19.

20.

21.

22.

23.

24.

25.

26.

#—chiral center is (R), (S) or racemate.

Other esters that are suitable for use herein are described in EP632048.

Protecting groups also includes “double ester” formingprofunctionalities such as —CH₂OC(O)OCH₃,

—CH₂OCON(CH₃)₂, or alkyl- or aryl-acyloxyalkyl groups of the structure—CH(R¹ or W⁵)O((CO)R³⁷) or —CH(R¹ or W⁵)((CO)OR³⁸) (linked to oxygen ofthe acidic group) wherein R³⁷ and R³⁸ are alkyl, aryl, or alkylarylgroups (see U.S. Pat. No. 4,968,788). Frequently R³⁷ and R³⁸ are bulkygroups such as branched alkyl, ortho-substituted aryl, meta-substitutedaryl, or combinations thereof, including normal, secondary, iso- andtertiary alkyls of 1-6 carbon atoms. An example is the pivaloyloxymethylgroup. These are of particular use with prodrugs for oraladministration. Examples of such useful protecting groups arealkylacyloxymethyl esters and their derivatives, including—CH(CH₂CH₂OCH₃)OC(O)C(CH₃)₃,

CH₂OC(O)C₁₀H₁₅, —CH₂OC(O)C(CH₃)₃, —CH(CH₂OCH₃)OC(O)C(CH₃)₃,—CH(CH(CH₃)₂)OC(O)C(CH₃)₃, —CH₂OC(O)CH₂CH(CH₃)₂, —CH₂OC(O)C₆H₁₁,—CH₂OC(O)C₆H₅, —CH₂OC(O)C₁₀H₁₅, —CH₂OC(O)CH₂CH₃, —CH₂OC(O)CH(CH₃)₂,—CH₂OC(O)C(CH₃)₃ and —CH₂OC(O)CH₂C₆H₅.

In some claims the protected acidic group is an ester of the acidicgroup and is the residue of a hydroxyl-containing functionality. Inother claims, an amino compound is used to protect the acidfunctionality. The residues of suitable hydroxyl or amino-containingfunctionalities are set forth above or are found in WO 95/07920. Ofparticular interest are the residues of amino acids, amino acid esters,polypeptides, or aryl alcohols. Typical amino acid, polypeptide andcarboxyl-esterified amino acid residues are described on pages 11-18 andrelated text of WO 95/07920 as groups L1 or L2. WO 95/07920 expresslyteaches the amidates of phosphonic acids, but it will be understood thatsuch amidates are formed with any of the acid groups set forth hereinand the amino acid residues set forth in WO 95/07920.

Typical esters for protecting acidic functionalities are also describedin WO 95/07920, again understanding that the same esters can be formedwith the acidic groups herein as with the phosphonate of the '920publication. Typical ester groups are defined at least on WO 95/07920pages 89-93 (under R³¹ or R³⁵), the table on page 105, and pages 21-23(as R). Of particular interest are esters of unsubstituted aryl such asphenyl or arylalkyl such benzyl, or hydroxy-, halo-, alkoxy-, carboxy-and/or alkylestercarboxy-substituted aryl or alkylaryl, especiallyphenyl, ortho-ethoxyphenyl, or C₁-C₄ alkylestercarboxyphenyl (salicylateC₁-C₁₂ alkylesters).

The protected acidic groups, particularly when using the esters oramides of WO 95/07920, are useful as prodrugs for oral administration.However, it is not essential that the acidic group be protected in orderfor the compounds of this invention to be effectively administered bythe oral route. When the compounds of the invention having protectedgroups, in particular amino acid amidates or substituted andunsubstituted aryl esters are administered systemically or orally theyare capable of hydrolytic cleavage in vivo to yield the free acid.

One or more of the acidic hydroxyls are protected. If more than oneacidic hydroxyl is protected then the same or a different protectinggroup is employed, e.g., the esters may be different or the same, or amixed amidate and ester may be used.

Typical hydroxy protecting groups described in Greene (pages 14-118)include substituted methyl and alkyl ethers, substituted benzyl ethers,silyl ethers, esters including sulfonic acid esters, and carbonates. Forexample:

-   -   Ethers (methyl, t-butyl, allyl);    -   Substituted Methyl Ethers (Methoxymethyl, Methylthiomethyl,        t-Butylthiomethyl, (Phenyldimethylsilyl)methoxymethyl,        Benzyloxymethyl, p-Methoxybenzyloxymethyl,        (4-Methoxyphenoxy)methyl, Guaiacolmethyl, t-Butoxymethyl,        4-Pentenyloxymethyl, Siloxymethyl, 2-Methoxyethoxymethyl,        2,2,2-Trichloroethoxymethyl, Bis(2-chloroethoxy)methyl,        2-(Trimethylsilyl)ethoxymethyl, Tetrahydropyranyl,        3-Bromotetrahydropyranyl, Tetrahydropthiopyranyl,        1-Methoxycyclohexyl, 4-Methoxytetrahydropyranyl,        4-Methoxytetrahydrothiopyranyl, 4-Methoxytetrahydropthiopyranyl        S,S-Dioxido,        1-[(2-Chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl,        1,4-Dioxan-2-yl, Tetrahydrofuranyl, Tetrahydrothiofuranyl,        2,3,3a,4,5,6,7,7a-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl));    -   Substituted Ethyl Ethers (1-Ethoxyethyl,        1-(2-Chloroethoxy)ethyl, 1-Methyl-1-methoxyethyl,        1-Methyl-1-benzyloxyethyl, 1-Methyl-1-benzyloxy-2-fluoroethyl,        2,2,2-Trichloroethyl, 2-Trimethylsilylethyl,        2-(Phenylselenyl)ethyl;    -   p-Chlorophenyl, p-Methoxyphenyl, 2,4-Dinitrophenyl, Benzyl);    -   Substituted Benzyl Ethers (p-Methoxybenzyl, 3,4-Dimethoxybenzyl,        o-Nitrobenzyl, p-Nitrobenzyl, p-Halobenzyl, 2,6-Dichlorobenzyl,        p-Cyanobenzyl, p-Phenylbenzyl, 2- and 4-Picolyl,        3-Methyl-2-picolyl N-Oxido, Diphenylmethyl,        p,p′-Dinitrobenzhydryl, 5-Dibenzosuberyl, Triphenylmethyl,        α-Naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl,        Di(p-methoxyphenyl)phenylmethyl, Tri(p-methoxyphenyl)methyl,        4-(4′-Bromophenacyloxy)phenyldiphenylmethyl,        4,4′,4″-Tris(4,5-dichlorophthalimidophenyl)methyl,        4,4′,4″-Tris(levulinoyloxyphenyl)methyl,        4,4′,4″-Tris(benzoyloxyphenyl)methyl,        3-(Imidazol-1-ylmethyl)bis(4′,4″-dimethoxyphenyl)methyl,        1,1-Bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-Anthryl,        9-(9-Phenyl)xanthenyl, 9-(9-Phenyl-10-oxo)anthryl,        1,3-Benzodithiolan-2-yl, Benzisothiazolyl S,S-Dioxido);    -   Silyl Ethers (Trimethylsilyl, Triethylsilyl, Triisopropylsilyl,        Dimethylisopropylsilyl, Diethylisopropylsilyl,        Dimethylthexylsilyl, t-Butyldimethylsilyl, t-Butyldiphenylsilyl,        Tribenzylsilyl, Tri-p-xylylsilyl, Triphenylsilyl,        Diphenylmethylsilyl, t-Butylinethoxyphenylsilyl);    -   Esters (Formate, Benzoylformate, Acetate, Choroacetate,        Dichloroacetate, Trichloroacetate, Trifluoroacetate,        Methoxyacetate, Triphenylmethoxyacetate, Phenoxyacetate,        p-Chlorophenoxyacetate, p-poly-Phenylacetate,        3-Phenylpropionate, 4-Oxopentanoate (Levulinate),        4,4-(Ethylenedithio)pentanoate, Pivaloate, Adamantoate,        Crotonate, 4-Methoxycrotonate, Benzoate, p-Phenylbenzoate,        2,4,6-Trimethylbenzoate (Mesitoate));    -   Carbonates (Methyl, 9-Fluorenylmethyl, Ethyl,        2,2,2-Trichloroethyl, 2-(Trimethylsilyl)ethyl,        2-(Phenylsulfonyl)ethyl, 2-(Triphenylphosphonio)ethyl, Isobutyl,        Vinyl, Allyl, p-Nitrophenyl, Benzyl, p-Methoxybenzyl,        3,4-Dimethoxybenzyl, o-Nitrobenzyl, p-Nitrobenzyl, S-Benzyl        Thiocarbonate, 4-Ethoxy-1-naphthyl, Methyl Dithiocarbonate);    -   Groups With Assisted Cleavage (2-Iodobenzoate, 4-Azidobutyrate,        4-Nitro-4-methylpentanoate, o-(Dibromomethyl)benzoate,        2-Formylbenzenesulfonate, 2-(Methylthiomethoxy)ethyl Carbonate,        4-(Methylthiomethoxy)butyrate,        2-(Methylthiomethoxymethyl)benzoate); Miscellaneous Esters        (2,6-Dichloro-4-methylphenoxyacetate, 2,6-Dichloro-4-(1,1,3,3        tetramethylbutyl)phenoxyacetate,        2,4-Bis(1,1-dimethylpropyl)phenoxyacetate,        Chlorodiphenylacetate, Isobutyrate, Monosuccinate,        (E)-2-Methyl-2-butenoate (Tigloate),        o-(Methoxycarbonyl)benzoate, p-poly-Benzoate, α-Naphthoate,        Nitrate, Alkyl N,N,N′,N′-Tetramethylphosphorodiamidate,        N-Phenylcarbamate, Borate, Dimethylphosphinothioyl,        2,4-Dinitrophenylsulfenate); and    -   Sulfonates (Sulfate, Methanesulfonate (Mesylate),        Benzylsulfonate, Tosylate).

Typical 1,2-diol protecting groups (thus, generally where two OH groupsare taken together with the protecting functionality) are described inGreene at pages 118-142 and include Cyclic Acetals and Ketals(Methylene, Ethylidene, 1-t-Butylethylidene, 1-Phenylethylidene,(4-Methoxyphenyl)ethylidene, 2,2,2-Trichloroethylidene, Acetonide(Isopropylidene), Cyclopentylidene, Cyclohexylidene, Cycloheptylidene,Benzylidene, p-Methoxybenzylidene, 2,4-Dimethoxybenzylidene,3,4-Dimethoxybenzylidene, 2-Nitrobenzylidene); Cyclic Ortho Esters(Methoxymethylene, Ethoxymethylene, Dimethoxymethylene,1-Methoxyethylidene, 1-Ethoxyethylidine, 1,2-Dimethoxyethylidene,α-Methoxybenzylidene, 1-(N,N-Dimethylamino)ethylidene Derivative,α-(N,N-Dimethylamino)benzylidene Derivative, 2-Oxacyclopentylidene);Silyl Derivatives (Di-t-butylsilylene Group,1,3-(1,1,3,3-Tetraisopropyldisiloxanylidene), andTetra-t-butoxydisiloxane-1,3-diylidene), Cyclic Carbonates, CyclicBoronates, Ethyl Boronate and Phenyl Boronate.

More typically, 1,2-diol protecting groups include those shown in TableB, still more typically, epoxides, acetonides, cyclic ketals and arylacetals.

TABLE B

wherein R⁹ is C₁-C₆ alkyl.

Amino Protecting Groups

Another set of protecting groups include any of the typical aminoprotecting groups described by Greene at pages 315-385. They include:

-   -   Carbamates: (methyl and ethyl, 9-fluorenylmethyl,        9(2-sulfo)fluorenylmethyl, 9-(2,7-dibromo)fluorenylmethyl,        2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl,        4-methoxyphenacyl);    -   Substituted Ethyl: (2,2,2-trichoroethyl, 2-trimethylsilylethyl,        2-phenylethyl, 1-(1-adamantyl)-1-methylethyl,        1,1-dimethyl-2-haloethyl, 1,1-dimethyl-2,2-dibromoethyl,        1,1-dimethyl-2,2,2-trichloroethyl,        1-methyl-1-(4-biphenylyl)ethyl,        1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2′- and        4′-pyridyl)ethyl, 2-(N,N-dicyclohexylcarboxamido)ethyl, t-butyl,        1-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamyl,        4-nitrocinnamyl, 8-quinolyl, N-hydroxypiperidinyl, alkyldithio,        benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl,        p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl,        9-anthrylmethyl, diphenylmethyl);    -   Groups With Assisted Cleavage: (2-methylthioethyl,        2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl,        [2-(1,3-dithianyl)]methyl, 4-methylthiophenyl,        2,4-dimethylthiophenyl, 2-phosphonioethyl,        2-triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl,        m-choro-p-acyloxybenzyl, p-(dihydroxyboryl)benzyl,        5-benzisoxazolylmethyl, 2-(trifluoromethyl)-6-chromonylmethyl);    -   Groups Capable of Photolytic Cleavage: (m-nitrophenyl,        3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl,        phenyl(o-nitrophenyl)methyl); Urea-Type Derivatives        (phenothiazinyl-(10)-carbonyl,        N′-p-toluenesulfonylaminocarbonyl, N′-phenylaminothiocarbonyl);    -   Miscellaneous Carbamates: (t-amyl, S-benzyl thiocarbamate,        p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl,        cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl,        2,2-dimethoxycarbonylvinyl, o-(N,N-dimethylcarboxamido)benzyl,        1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl,        1,1-dimethylpropynyl, di(2-pyridyl)methyl, 2-furanylmethyl,        2-Iodoethyl, Isobornyl, Isobutyl, Isonicotinyl,        p-(p′-Methoxyphenylazo)benzyl, 1-methylcyclobutyl,        1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl,        1-methyl-1-(3,5-dimethoxyphenyl)ethyl,        1-methyl-1-(p-phenylazophenyl)ethyl, 1-methyl-1-phenylethyl,        1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl,        2,4,6-tri-t-butylphenyl, 4-(trimethylammonium)benzyl,        2,4,6-trimethylbenzyl);    -   Amides: (N-formyl, N-acetyl, N-choroacetyl, N-trichoroacetyl,        N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl,        N-picolinoyl, N-3-pyridylcarboxamide, N-benzoylphenylalanyl,        N-benzoyl, N-p-phenylbenzoyl);    -   Amides With Assisted Cleavage: (N-o-nitrophenylacetyl,        N-o-nitrophenoxyacetyl, N-acetoacetyl,        (N′-dithiobenzyloxycarbonylamino)acetyl,        N-3-(p-hydroxyphenyl)propionyl, N-3-(o-nitrophenyl)propionyl,        N-2-methyl-2-(o-nitrophenoxy)propionyl,        N-2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl,        N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl,        N-acetylmethionine, N-o-nitrobenzoyl,        N-o-(benzoyloxymethyl)benzoyl, 4,5-diphenyl-3-oxazolin-2-one);    -   Cyclic Imide Derivatives: (N-phthalimide, N-dithiasuccinoyl,        N-2,3-diphenylmaleoyl, N-2,5-dimethylpyrrolyl,        N-1,1,4,4-tetramethyldisilylazacyclopentane adduct,        5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one,        5-substituted 1,3-dibenzyl-1,3-5-triazacyclohexan-2-one,        1-substituted 3,5-dinitro-4-pyridonyl);    -   N-Alkyl and N-Aryl Amines: (N-methyl, N-allyl,        N-[2-(trimethylsilyl)ethoxy]methyl, N-3-acetoxypropyl,        N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl), Quaternary        Ammonium Salts, N-benzyl, N-di(4-methoxyphenyl)methyl,        N-5-dibenzosuberyl, N-triphenylmethyl,        N-(4-methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl,        N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl,        N-2-picolylamine N′-oxide);    -   Imine Derivatives: (N-1,1-dimethylthiomethylene, N-benzylidene,        N-p-methoxybenzylidene, N-diphenylmethylene,        N-[(2-pyridyl)mesityl]methylene,        N,(N′,N′-dimethylaminomethylene, N,N′-isopropylidene,        N-p-nitrobenzylidene, N-salicylidene, N-5-chlorosalicylidene,        N-(5-chloro-2-hydroxyphenyl)phenylmethylene, N-cyclohexylidene);    -   Enamine Derivatives: (N-(5,5-dimethyl-3-oxo-1-cyclohexenyl));    -   N-Metal Derivatives (N-borane derivatives, N-diphenylborinic        acid derivatives, N-[phenyl(pentacarbonylchromium- or        -tungsten)]carbenzyl, N-copper or N-zinc chelate);    -   N—N Derivatives: (N-nitro, N-nitroso, N-oxide);    -   N—P Derivatives: (N-diphenylphosphinyl,        N-dimethylthiophosphinyl, N-diphenylthiophosphinyl, N-dialkyl        phosphoryl, N-dibenzyl phosphoryl, N-diphenyl phosphoryl);    -   N—Si Derivatives, N—S Derivatives, and N-Sulfenyl Derivatives:        (N-benzenesulfenyl, N-o-nitrobenzenesulfenyl,        N-2,4-dinitrobenzenesulfenyl, N-pentachlorobenzenesulfenyl,        N-2-nitro-4-methoxybenzenesulfenyl, N-triphenylmethylsulfenyl,        N-3-nitropyridinesulfenyl); and N-sulfonyl Derivatives        (N-p-toluenesulfonyl, N-benzenesulfonyl,        N-2,3,6-trimethyl-4-methoxybenzenesulfonyl,        N-2,4,6-trimethoxybenzenesulfonyl,        N-2,6-dimethyl-4-methoxybenzenesulfonyl,        N-pentamethylbenzenesulfonyl,        N-2,3,5,6,-tetramethyl-4-methoxybenzenesulfonyl,        N-4-methoxybenzenesulfonyl, N-2,4,6-trimethylbenzenesulfonyl,        N-2,6-dimethoxy-4-methylbenzenesulfonyl,        N-2,2,5,7,8-pentamethylchroman-6-sulfonyl, N-methanesulfonyl,        N-β-trimethylsilyethanesulfonyl, N-9-anthracenesulfonyl,        N-4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonyl,        N-benzylsulfonyl, N-trifluoromethylsulfonyl,        N-phenacylsulfonyl).

More typically, protected amino groups include carbamates and amides,still more typically, —NHC(O)R¹ or —N═CR¹N(R¹)₂. Another protectinggroup, also useful as a prodrug for amino or —NH(R⁵), is:

See for example Alexander, J. et al. (1996) J. Med. Chem. 39:480-486.

Amino Acid and Polypeptide Protecting Group and Conjugates

An amino acid or polypeptide protecting group of a compound of theinvention has the structure R¹⁵NHCH(R¹⁶)C(O)—, where R¹⁵ is H, an aminoacid or polypeptide residue, or R⁵, and R¹⁶ is defined below.

R¹⁶ is lower alkyl or lower alkyl (C₁-C₆) substituted with amino,carboxyl, amide, carboxyl ester, hydroxyl, C₆-C₇ aryl, guanidinyl,imidazolyl, indolyl, sulfhydryl, sulfoxide, and/or alkylphosphate. R¹⁰also is taken together with the amino acid a N to form a proline residue(R¹⁰=—CH₂)₃—). However, R¹⁰ is generally the side group of anaturally-occurring amino acid such as H, —CH₃, —CH(CH₃)₂,—CH₂—CH(CH₃)₂, —CHCH₃—CH₂—CH₃, —CH₂—C₆H₅, —CH₂CH₂—S—CH₃, —CH₂OH,—CH(OH)—CH₃, —CH₂—SH, —CH₂—C₆H₄OH, —CH₂—CO—NH₂, —CH₂—CH₂—CO—NH₂,—CH₂—COOH, —CH₂—CH₂—COOH, —(CH₂)₄—NH₂ and —(CH₂)₃—NH—C(NH₂)—NH₂. R₁₀also includes 1-guanidinoprop-3-yl, benzyl, 4-hydroxybenzyl,imidazol-4-yl, indol-3-yl, methoxyphenyl and ethoxyphenyl.

Another set of protecting groups include the residue of anamino-containing compound, in particular an amino acid, a polypeptide, aprotecting group, —NHSO₂R, NHC(O)R, —N(R)₂, NH₂ or —NH(R)(H), wherebyfor example a carboxylic acid is reacted, i.e. coupled, with the amineto form an amide, as in C(O)NR₂. A phosphonic acid may be reacted withthe amine to form a phosphonamidate, as in —P(O)(OR)(NR₂).

In general, amino acids have the structure R¹⁷C(O)CH(R¹⁶)NH—, where R¹⁷is —OH, —OR, an amino acid or a polypeptide residue. Amino acids are lowmolecular weight compounds, on the order of less than about 1000 MW andwhich contain at least one amino or imino group and at least onecarboxyl group. Generally the amino acids will be found in nature, i.e.,can be detected in biological material such as bacteria or othermicrobes, plants, animals or man. Suitable amino acids typically arealpha amino acids, i.e. compounds characterized by one amino or iminonitrogen atom separated from the carbon atom of one carboxyl group by asingle substituted or unsubstituted alpha carbon atom. Of particularinterest are hydrophobic residues such as mono- or di-alkyl or arylamino acids, cycloalkylamino acids and the like. These residuescontribute to cell permeability by increasing the partition coefficientof the parental drug. Typically, the residue does not contain asulfhydryl or guanidino substituent.

Naturally-occurring amino acid residues are those residues foundnaturally in plants, animals or microbes, especially proteins thereof.Polypeptides most typically will be substantially composed of suchnaturally-occurring amino acid residues. These amino acids are glycine,alanine, valine, leucine, isoleucine, serine, threonine, cysteine,methionine, glutamic acid, aspartic acid, lysine, hydroxylysine,arginine, histidine, phenylalanine, tyrosine, tryptophan, proline,asparagine, glutamine and hydroxyproline. Additionally, unnatural aminoacids, for example, valanine, phenylglycine and homoarginine are alsoincluded. Commonly encountered amino acids that are not gene-encoded mayalso be used in the present invention. All of the amino acids used inthe present invention may be either the D- or L-optical isomer. Inaddition, other peptidomimetics are also useful in the presentinvention. For a general review, see Spatola, A. F., in Chemistry andBiochemistry of Amino Acids, Peptides and Proteins, B. Weinstein, eds.,Marcel Dekker, New York, p. 267 (1983).

When protecting groups are single amino acid residues or polypeptidesthey optionally are substituted at R³ of substituents A¹, A² or A³ in acompound of the invention. These conjugates are produced by forming anamide bond between a carboxyl group of the amino acid (or C-terminalamino acid of a polypeptide for example). Similarly, conjugates areformed between R³ and an amino group of an amino acid or polypeptide.Generally, only one of any site in the parental molecule is amidatedwith an amino acid as described herein, although it is within the scopeof this invention to introduce amino acids at more than one permittedsite. Usually, a carboxyl group of R³ is amidated with an amino acid. Ingeneral, the α-amino or α-carboxyl group of the amino acid or theterminal amino or carboxyl group of a polypeptide are bonded to theparental functionalities, i.e., carboxyl or amino groups in the aminoacid side chains generally are not used to form the amide bonds with theparental compound (although these groups may need to be protected duringsynthesis of the conjugates as described further below).

With respect to the carboxyl-containing side chains of amino acids orpolypeptides it will be understood that the carboxyl group optionallywill be blocked, e.g., by R¹, esterified with R⁵ or amidated. Similarly,the amino side chains R¹⁶ optionally will be blocked with R¹ orsubstituted with R⁵.

Such ester or amide bonds with side chain amino or carboxyl groups, likethe esters or amides with the parental molecule, optionally arehydrolyzable in vivo or in vitro under acidic (pH<3) or basic (pH>10)conditions. Alternatively, they are substantially stable in thegastrointestinal tract of humans but are hydrolyzed enzymatically inblood or in intracellular environments. The esters or amino acid orpolypeptide amidates also are useful as intermediates for thepreparation of the parental molecule containing free amino or carboxylgroups. The free acid or base of the parental compound, for example, isreadily formed from the esters or amino acid or polypeptide conjugatesof this invention by conventional hydrolysis procedures.

When an amino acid residue contains one or more chiral centers, any ofthe D, L, meso, threo or erythro (as appropriate) racemates, scalematesor mixtures thereof may be used. In general, if the intermediates are tobe hydrolyzed non-enzymatically (as would be the case where the amidesare used as chemical intermediates for the free acids or free amines), Disomers are useful. On the other hand, L isomers are more versatilesince they can be susceptible to both non-enzymatic and enzymatichydrolysis, and are more efficiently transported by amino acid ordipeptidyl transport systems in the gastrointestinal tract.

Examples of suitable amino acids whose residues are represented by R^(x)or R^(y) include the following:

Glycine;

Aminopolycarboxylic acids, e.g., aspartic acid, β-hydroxyaspartic acid,glutamic acid, β-hydroxyglutamic acid, β-methylaspartic acid,β-methylglutamic acid, β,β-dimethylaspartic acid, γ-hydroxyglutamicacid, β,γ-dihydroxyglutamic acid, β-phenylglutamic acid,γ-methyleneglutamic acid, 3-aminoadipic acid, 2-aminopimelic acid,2-aminosuberic acid and 2-aminosebacic acid;

Amino acid amides such as glutamine and asparagine;

Polyamino- or polybasic-monocarboxylic acids such as arginine, lysine,β-aminoalanine, γ-aminobutyrine, ornithine, citruline, homoarginine,homocitrulline, hydroxylysine, allohydroxylsine and diaminobutyric acid;

Other basic amino acid residues such as histidine;

Diaminodicarboxylic acids such as α,α′-diaminosuccinic acid,α,α′-diaminoglutaric acid, α,α′-diaminoadipic acid, α,α′-diaminopimelicacid, α,α′-diamino-β-hydroxypimelic acid, α,α′-diaminosuberic acid,α,α′-diaminoazelaic acid, and α,α′-diaminosebacic acid;

Imino acids such as proline, hydroxyproline, allohydroxyproline,γ-methylproline, pipecolic acid, 5-hydroxypipecolic acid, andazetidine-2-carboxylic acid;

A mono- or di-alkyl (typically C₁-C₈ branched or normal) amino acid suchas alanine, valine, leucine, allylglycine, butyrine, norvaline,norleucine, heptyline, α-methylserine, α-amino-α-methyl-γ-hydroxyvalericacid, α-amino-α-methyl-δ-hydroxyvaleric acid,α-amino-α-methyl-ε-hydroxycaproic acid, isovaline, α-methylglutamicacid, α-aminoisobutyric acid, α-aminodiethylacetic acid,α-aminodiisopropylacetic acid, α-aminodi-n-propylacetic acid,α-aminodiisobutylacetic acid, α-aminodi-n-butylacetic acid,α-aminoethylisopropylacetic acid, α-amino-n-propylacetic acid,α-aminodiisoamyacetic acid, α-methylaspartic acid, α-methylglutamicacid, 1-aminocyclopropane-1-carboxylic acid, isoleucine, alloisoleucine,tert-leucine, β-methyltryptophan and α-amino-β-ethyl-β-phenylpropionicacid;

β-phenylserinyl;

Aliphatic α-amino-β-hydroxy acids such as serine, β-hydroxyleucine,β-hydroxynorleucine, β-hydroxynorvaline, and α-amino-β-hydroxystearicacid;

α-Amino, α-, γ-, δ- or ε-hydroxy acids such as homoserine,ε-hydroxynorvaline, γ-hydroxynorvaline and ε-hydroxynorleucine residues;canavine and canaline; γ-hydroxyornithine;

2-hexosaminic acids such as D-glucosaminic acid or D-galactosaminicacid;

α-Amino-β-thiols such as penicillamine, β-thiolnorvaline orβ-thiolbutyrine;

Other sulfur containing amino acid residues including cysteine;homocystine, β-phenylmethionine, methionine, S-allyl-L-cysteinesulfoxide, 2-thiolhistidine, cystathionine, and thiol ethers of cysteineor homocysteine;

Phenylalanine, tryptophan and ring-substituted α-amino acids such as thephenyl- or cyclohexylamino acids α-aminophenylacetic acid,α-aminocyclohexylacetic acid and α-amino-β-cyclohexylpropionic acid;phenylalanine analogues and derivatives comprising aryl, lower alkyl,hydroxy, guanidino, oxyalkylether, nitro, sulfur or halo-substitutedphenyl (e.g., tyrosine, methyltyrosine and o-chloro-, p-chloro-,3,4-dichloro, o-, m- or p-methyl-, 2,4,6-trimethyl-, 2-ethoxy-5-nitro-,2-hydroxy-5-nitro- and p-nitro-phenylalanine); furyl-, thienyl-,pyridyl-, pyrimidinyl-, purinyl- or naphthyl-alanines; and tryptophananalogues and derivatives including kynurenine, 3-hydroxykynurenine,2-hydroxytryptophan and 4-carboxytryptophan;

α-Amino substituted amino acids including sarcosine (N-methylglycine),N-benzylglycine, N-methylalanine, N-benzylalanine,N-methylphenylalaninc, N-benzylphenylalanine, N-methylvaline andN-benzylvaline; and

α-Hydroxy and substituted α-hydroxy amino acids including serine,threonine, allothreonine, phosphoserine and phosphothreonine.

Polypeptides are polymers of amino acids in which a carboxyl group ofone amino acid monomer is bonded to an amino or imino group of the nextamino acid monomer by an amide bond. Polypeptides include dipeptides,low molecular weight polypeptides (about 1500-5000 MW) and proteins.Proteins optionally contain 3, 5, 10, 50, 75, 100 or more residues, andsuitably are substantially sequence-homologous with human, animal, plantor microbial proteins. They include enzymes (e.g., hydrogen peroxidase)as well as immunogens such as KLH, or antibodies or proteins of any typeagainst which one wishes to raise an immune response. The nature andidentity of the polypeptide may vary widely.

The polypeptide amidates are useful as immunogens in raising antibodiesagainst either the polypeptide (if it is not immunogenic in the animalto which it is administered) or against the epitopes on the remainder ofthe compound of this invention.

Antibodies capable of binding to the parental non-peptidyl compound areused to separate the parental compound from mixtures, for example indiagnosis or manufacturing of the parental compound. The conjugates ofparental compound and polypeptide generally are more immunogenic thanthe polypeptides in closely homologous animals, and therefore make thepolypeptide more immunogenic for facilitating raising antibodies againstit. Accordingly, the polypeptide or protein may not need to beimmunogenic in an animal typically used to raise antibodies, e.g.,rabbit, mouse, horse, or rat, but the final product conjugate should beimmunogenic in at least one of such animals. The polypeptide optionallycontains a peptidolytic enzyme cleavage site at the peptide bond betweenthe first and second residues adjacent to the acidic heteroatom. Suchcleavage sites are flanked by enzymatic recognition structures, e.g., aparticular sequence of residues recognized by a peptidolytic enzyme.

Peptidolytic enzymes for cleaving the polypeptide conjugates of thisinvention are well known, and in particular include carboxypeptidases.Carboxypeptidases digest polypeptides by removing C-terminal residues,and are specific in many instances for particular C-terminal sequences.Such enzymes and their substrate requirements in general are well known.For example, a dipeptide (having a given pair of residues and a freecarboxyl terminus) is covalently bonded through its α-amino group to thephosphorus or carbon atoms of the compounds herein. In claims where W₁is phosphonate it is expected that this peptide will be cleaved by theappropriate peptidolytic enzyme, leaving the carboxyl of the proximalamino acid residue to autocatalytically cleave the phosphonoamidatebond.

Suitable dipeptidyl groups (designated by their single letter code) areAA, AR, AN, AD, AC, AE, AQ, AG, AH, AI, AL, AK, AM, AF, AP, AS, AT, AW,AY, AV, RA, RR, RN, RD, RC, RE, RQ, RG, RH, RI, RL, RK, RM, RF, RP, RS,RT, RW, RY, RV, NA, NR, NN, ND, NC, NE, NQ, NG, NH, NI, NL, NK, NM, NF,NP, NS, NT, NR, NY, NV, DA, DR, DN, DD, DC, DE, DQ, DG, DH, DI, DL, DK,DM, DF, DP, DS, DT, DW, DY, DV, CA, CR, CN, CD, CC, CE, CQ, CG, CH, CI,CL, CK, CM, CF, CP, CS, CT, CW, CY, CV, EA, ER, EN, ED, EC, EE, EQ, EG,EH, EI, EL, EK, EM, EF, EP, ES, ET, EW, EY, EV, QA, QR, QN, QD, QC, QE,QQ, QG, QH, QI, QL, QK, QM, QF, QP, QS, QT, QW, QY, QV, GA, GR, GN, GD,GC, GE, GQ, GG, GH, GI, GL, GK, GM, GF, GP, GS, GT, GW, GY, GV, HA, HR,HN, HD, HC, HE, HQ, HG, HH, HI, HL, HK, HM, HF, HP, HS, HT, HW, HY, HV,IA, IR, IN, ID, IC, IE, IQ, IG, IH, II, IL, IK, IM, IF, IP, IS, IT, IW,IY, IV, LA, LR, LN, LD, LC, LE, LQ, LG, LH, LI, LL, LK, LM, LF, LP, LS,LT, LW, LY, LV, KA, KR, KN, KD, KC, KE, KQ, KG, KH, KI, KL, KK, KM, KF,KP, KS, KT, KW, KY, KV, MA, MR, MN, MD, MC, ME, MQ, MG, MH, MI, ML, MK,MM, MF, MP, MS, MT, MW, MY, MV, FA, FR, FN, FD, FC, FE, FQ, FG, FH, FI,FL, FK, FM, FF, FP, FS, FT, FW, FY, FV, PA, PR, PN, PD, PC, PE, PQ, PG,PH, PI, PL, PK, PM, PF, PP, PS, PT, PW, PY, PV, SA, SR, SN, SD, SC, SE,SQ, SG, SH, SI, SL, SK, SM, SF, SP, SS, ST, SW, SY, SV, TA, TR, TN, TD,TC, TE, TQ, TG, TH, TI, TL, TK, TM, TF, TP, TS, TT, TW, TY, TV, WA, WR,WN, WD, WC, WE, WQ, WG, WH, WI, WL, WK, WM, WF, WP, WS, WT, WW, WY, WV,YA, YR, YN, YD, YC, YE, YQ, YG, YH, YI, YL, YK, YM, YF, YP, YS, YT, YW,YY, YV, VA, VR, VN, VD, VC, VE, VQ, VG, VH, VI, VL, VK, VM, VF, VP, VS,VT, VW, VY and VV.

Tripeptide residues are also useful as protecting groups. When aphosphonate is to be protected, the sequence —X⁴-pro-X⁵— (where X⁴ isany amino acid residue and X⁵ is an amino acid residue, a carboxyl esterof proline, or hydrogen) will be cleaved by luminal carboxypeptidase toyield X⁴ with a free carboxyl, which in turn is expected toautocatalytically cleave the phosphonoamidate bond. The carboxy group ofX⁵ optionally is esterified with benzyl.

Dipeptide or tripeptide species can be selected on the basis of knowntransport properties and/or susceptibility to peptidases that can affecttransport to intestinal mucosal or other cell types. Dipeptides andtripeptides lacking an α-amino group are transport substrates for thepeptide transporter found in brush border membrane of intestinal mucosalcells (Bai, J. P. F., (1992) Pharm Res. 9:969-978). Transport competentpeptides can thus be used to enhance bioavailability of the amidatecompounds. Di- or tripeptides having one or more amino acids in the Dconfiguration are also compatible with peptide transport and can beutilized in the amidate compounds of this invention. Amino acids in theD configuration can be used to reduce the susceptibility of a di- ortripeptide to hydrolysis by proteases common to the brush border such asaminopeptidase N. In addition, di- or tripeptides alternatively areselected on the basis of their relative resistance to hydrolysis byproteases found in the lumen of the intestine. For example, tripeptidesor polypeptides lacking asp and/or glu are poor substrates foraminopeptidase A, di- or tripeptides lacking amino acid residues on theN-terminal side of hydrophobic amino acids (leu, tyr, phe, val, trp) arepoor substrates for endopeptidase, and peptides lacking a pro residue atthe penultimate position at a free carboxyl terminus are poor substratesfor carboxypeptidase P. Similar considerations can also be applied tothe selection of peptides that are either relatively resistant orrelatively susceptible to hydrolysis by cytosolic, renal, hepatic, serumor other peptidases. Such poorly cleaved polypeptide amidates areimmunogens or are useful for bonding to proteins in order to prepareimmunogens.

SPECIFIC EMBODIMENTS OF THE INVENTION

Specific values described for radicals, substituents, and ranges, aswell as specific embodiments of the invention described herein, are forillustration only; they do not exclude other defined values or othervalues within defined ranges.

In one specific embodiment of the invention, the conjugate is a compoundthat is substituted with one or more phosphonate groups either directlyor indirectly through a linker; and that is optionally substituted withone or more groups A⁰; or a pharmaceutically acceptable salt thereof,wherein:

A⁰ is A¹, A² or W³;

A₁ is:

A² is:

A³ is:

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x)));

Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—;

R^(x) is independently H, R¹, W³, a protecting group, or the formula:

wherein:

R^(y) is independently H, W³, R² or a protecting group;

R¹ is independently H or alkyl of 1 to 18 carbon atoms;

R² is independently H, R¹, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups or taken together at a carbon atom,two R² groups form a ring of 3 to 8 carbons and the ring may besubstituted with 0 to 3 R³ groups;

R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is boundto a heteroatom, then R³ is R^(3c) or R^(3d);

R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;

R^(3b) is Y¹;

R^(3c) is R^(x), N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x), —S(O)₂R^(x),—S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x), —OC(Y¹)OR^(x),—OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), —N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x)));

R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

R^(5a) is independently alkylene of 1 to 18 carbon atoms, alkenylene of2 to 18 carbon atoms, or alkynylene of 2-18 carbon atoms any one ofwhich alkylene, alkenylene or alkynylene is substituted with 0-3 R³groups;

W³ is W⁴ or W⁵;

W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO₂R⁵, or —SO₂W⁵;

W⁵ is carbocycle or heterocycle wherein W⁵ is independently substitutedwith 0 to 3 R² groups;

W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;

M2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M1a, M1c, and M1d are independently 0 or 1; and

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

In another specific embodiment of the invention A¹ is of the formula:

In another specific embodiment of the invention A¹ is of the formula:

In another specific embodiment of the invention A¹ is of the formula:

In another specific embodiment of the invention A¹ is of the formula:

In another specific embodiment of the invention A¹ is of the formula:

and W^(5a) is a carbocycle or a heterocycle where W^(5a) isindependently substituted with 0 or 1 R² groups. A specific value forM12a is 1.

In another specific embodiment of the invention A¹ is of the formula:

In another specific embodiment of the invention A¹ is of the formula:

In another specific embodiment of the invention A¹ is of the formula:

wherein W^(5a) is a carbocycle independently substituted with 0 or 1 R²groups.

In another specific embodiment of the invention A¹ is of the formula:

wherein Y^(2b) is O or N(R²); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A¹ is of the formula:

wherein W^(5a) is a carbocycle independently substituted with 0 or 1 R²groups.

In another specific embodiment of the invention A¹ is of the formula:

wherein W^(5a) is a carbocycle or heterocycle where W^(5a) isindependently substituted with 0 or 1 R² groups.

In another specific embodiment of the invention A¹ is of the formula:

wherein Y^(2b) is O or N(R²); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In a specific embodiment of the invention A² is of the formula:

In another specific embodiment of the invention A² is of the formula:

In another specific embodiment of the invention M12b is 1.

In another specific embodiment of the invention e M12b is 0, Y² is abond and W⁵ is a carbocycle or heterocycle where W⁵ is optionally andindependently substituted with 1, 2, or 3 R² groups.

In another specific embodiment of the invention A² is of the formula:

wherein W^(5a) is a carbocycle or heterocycle where W^(5a) is optionallyand independently substituted with 1, 2, or 3 R² groups.

In another specific embodiment of the invention M12a is 1.

In another specific embodiment of the invention A² is selected fromphenyl, substituted phenyl, benzyl, substituted benzyl, pyridyl andsubstituted pyridyl.

In another specific embodiment of the invention A² is of the formula:

In another specific embodiment of the invention A² is of the formula:

In another specific embodiment of the invention M12b is 1.

In a specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(1a) is O or S; and Y^(2a) is O, N(R^(x)) or S.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R^(x)).

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R^(x)); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R^(x)); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention M12d is 1.

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention W⁵ is a carbocycle.

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention W⁵ is phenyl.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(1a) is O or S; and Y^(2a) is O, N(R^(x)) or S.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R^(x)).

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R^(x)); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention R¹ is H.

In another specific embodiment of the invention A³ is of the formula:

wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R²groups.

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(1a) is O or S; and Y^(2a) is O, N(R²) or S.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(1a) is O or S; Y^(2b) is O or N(R²); and Y^(2c) is O,N(R^(y)) or S.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(1a) is O or S; Y^(2b) is O or N(R²); Y^(2d) is O or N(R^(y));and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R²); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R²).

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(1a) is O or S; and Y^(2a) is O, N(R²) or S.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(1a) is O or S; Y^(2b) is O or N(R²); and Y^(2c) is O,N(R^(y)) or S.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(1a) is O or S; Y^(2b) is O or N(R²); Y^(2d) is O or N(R^(y));and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R²); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R²).

In another specific embodiment of the invention A³ is of the formula:

wherein: Y^(2b) is or N(R^(x)); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A³ is of the formula:

wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R²groups.

In another specific embodiment of the invention A³ is of the formula:

wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R²groups.

In another specific embodiment of the invention A³ is of the formula:

In a specific embodiment of the invention A⁰ is of the formula:

wherein each R is independently (C₁-C₆)alkyl.

In a specific embodiment of the invention R^(x) is independently H, R¹,W³, a protecting group, or the formula:

wherein:

R^(y) is independently H, W³, R² or a protecting group;

R¹ is independently H or alkyl of 1 to 18 carbon atoms;

R² is independently H, R¹, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups or taken together at a carbon atom,two R² groups form a ring of 3 to 8 carbons and the ring may besubstituted with 0 to 3 R³ groups.

In a specific embodiment of the invention R^(x) is of the formula:

wherein Y^(1a) is O or S; and Y^(2c) is O, N(R^(y)) or S.

In a specific embodiment of the invention R^(x) is of the formula:

wherein Y^(1a) is O or S; and Y^(2d) is O or N(R^(y)).

In a specific embodiment of the invention R^(x) is of the formula:

In a specific embodiment of the invention R^(y) is hydrogen or alkyl of1 to 10 carbons.

In a specific embodiment of the invention R^(x) is of the formula:

In a specific embodiment of the invention R^(x) is of the formula:

In a specific embodiment of the invention R^(x) is of the formula:

In a specific embodiment of the invention Y¹ is O or S.

In a specific embodiment of the invention Y² is O, N(R^(y)) or S.

In one specific embodiment of the invention R^(x) is a group of theformula:

wherein:

m1a, m1b, m1c, m1d and m1e are independently 0 or 1;

m12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

R^(y) is H, W³, R² or a protecting group;

provided that:

if m1a, m12c, and m1d are 0, then m1b, m1c and m1e are 0;

if m1a and m12c are 0 and m1d is not 0, then m1b and m1c are 0;

if m1a and m1d are 0 and m12c is not 0, then m1b and at least one of m1cand m1e are 0;

if m1a is 0 and m12c and m1d are not 0, then m1b is 0;

if m12c and m1d are 0 and m1a is not 0, then at least two of m1b, m1cand m1e are 0;

if m12c is 0 and m1a and m1d are not 0, then at least one of m1b and m1care 0; and

if m1d is 0 and m1a and m12c are not 0, then at least one of m1c and m1eare 0.

In another specific embodiment, the invention provides a compound of theformula:

[DRUG]-(A⁰)_(nn)

or a pharmaceutically acceptable salt thereof wherein,

DRUG is a compound of any one of formulae 500-523:

nn is 1, 2, or 3;

A⁰ is A¹, A² or W³ with the proviso that the compound includes at leastone A¹;

A¹ is:

A² is:

A³ is:

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x)));

Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—;

R^(x) is independently H, R¹, W³, a protecting group, or the formula:

wherein:

R^(y) is independently H, W³, R² or a protecting group;

R¹ is independently H or alkyl of 1 to 18 carbon atoms;

R² is independently H, R¹, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups or taken together at a carbon atom,two R² groups form a ring of 3 to 8 carbons and the ring may besubstituted with 0 to 3 R³ groups;

R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is boundto a heteroatom, then R³ is R^(3c) or R^(3d);

R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;

R^(3b) is Y¹;

R^(3c) is R^(x), N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x), —S(O)₂R^(x),—S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x), —OC(Y¹)OR^(x),OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x)));

R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

R^(5a) is independently alkylene of 1 to 18 carbon atoms, alkenylene of2 to 18 carbon atoms, or alkynylene of 2-18 carbon atoms any one ofwhich alkylene, alkenylene or alkynylene is substituted with 0-3 R³groups;

W³ is W⁴ or W⁵;

W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO₂R⁵, or SO₂W⁵;

W⁵ is carbocycle or heterocycle wherein W⁵ is independently substitutedwith 0 to 3 R² groups;

W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;

M2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M1a, M1c, and M1d are independently 0 or 1; and

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

In another specific embodiment, the invention provides a compound of theformula 1-51:

or a pharmaceutically acceptable salt thereof wherein:

A⁰ is A¹;

A¹ is:

A³ is:

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x)));

Y² is independently a bond O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—;

R^(x) is independently H, W³, a protecting group, or the formula:

R^(y) is independently H, W³, R² or a protecting group;

R¹ is independently H or alkyl of 1 to 18 carbon atoms;

R² is independently H, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups;

R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is boundto a heteroatom, then R³ is R^(3c) or R^(3d);

R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;

R^(3b) is Y¹;

R^(3c) is R^(x), N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x), —S(O)₂R^(x),—S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x), —OC(Y¹)OR^(x),—OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), —N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x)));

R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

R^(5a) is independently alkylene of 1 to 18 carbon atoms, alkenylene of2 to 18 carbon atoms, or alkynylene of 2-18 carbon atoms any one ofwhich alkylene, alkenylene or alkynylene is substituted with 0-3 R³groups;

W³ is W⁴ or W⁵;

W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO₂R⁵, or —SO₂W⁵;

W⁵ is carbocycle or heterocycle wherein W⁵ is independently substitutedwith 0 to 3 R² groups;

W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;

M2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M1a, M1c, and M1d are independently 0 or 1; and

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

The invention also provides a compound of any one of formulae I-51wherein:

A⁰ is A¹;

A¹ is:

A³ is:

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x)));

Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—;

R^(x) is independently H, W³, a protecting group, or the formula:

R^(y) is independently H, W³, R² or a protecting group;

R¹ is independently H or alkyl of 1 to 18 carbon atoms;

R² is independently H, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups;

R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is boundto a heteroatom, then R³ is R^(3c) or R^(3d);

R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;

R^(3b) is Y¹;

R^(3c) is R^(x), —N(R^(x))(R^(x)), —SR^(x)—S(O)R^(x), —S(O)₂R^(x),—S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x), —OC(Y¹)OR^(x),—OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), —N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x)));

R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

R^(5a) is independently alkylene of 1 to 18 carbon atoms, alkenylene of2 to 18 carbon atoms, or alkynylene of 2-18 carbon atoms any one ofwhich alkylene, alkenylene or alkynylene is substituted with 0-3 R³groups;

W³ is W⁴ or W⁵;

W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO₂R⁵, or —SO₂ W⁵;

W⁵ is carbocycle or heterocycle wherein W⁵ is independently substitutedwith 0 to 3 R² groups;

W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;

M2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M1a, M1c, and M1d are independently 0 or 1; and

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

In another specific embodiment, the invention provides a compound of theformula:

[DRUG]-[L-P(═Y¹)—Y²—R^(x)]_(nn)

or a pharmaceutically acceptable salt thereof wherein,

DRUG is a compound of any one of 500-523;

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x)));

Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—;

R^(x) is independently H, W³, a protecting group, or the formula:

R^(y) is independently H, W³, R² or a protecting group;

R² is independently H, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups;

R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is boundto a heteroatom, then R³ is R^(3c) or R^(3d);

R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;

R^(3b) is Y;

R^(3c) is R^(x), N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x), —S(O)₂R^(x),—S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x), —OC(Y¹)OR^(x),—OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), —N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x)));

R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

W³ is W⁴ or W⁵;

W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO₂R⁵, or —SO₂W⁵;

W⁵ is carbocycle or heterocycle wherein W⁵ is independently substitutedwith 0 to 3 R² groups;

M2 is 1, 2, or 3;

M1a, M1c, and M1d are independently 0 or 1;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

nn is 1, 2, or 3; and

L is a linking group.

In another specific embodiment, the invention provides a compound ofwhich is a compound of the formula:

[DRUG]-(A⁰)_(nn)

or a pharmaceutically acceptable salt thereof wherein,

DRUG is a compound of any one of formulae 500-523;

nn is 1, 2, or 3;

A⁰ is A¹, A², or W³ with the proviso that the compound includes at leastone A¹;

A¹ is:

A² is:

A³ is:

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x)));

Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—;

R^(x) is independently H, W³, a protecting group, or the formula:

R^(y) is independently H, W³, R² or a protecting group;

R² is independently H, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups;

R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is boundto a heteroatom, then R³ is R^(3c) or R^(3d);

R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;

R^(3b) is Y¹;

R^(3c) is R^(x), N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x), —S(O)₂R^(x),—S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x), —OC(Y¹)OR^(x),—OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), —N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x)));

R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

W³ is W⁴ or W⁵;

W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO₂R⁵, or —SO₂W⁵;

W⁵ is carbocycle or heterocycle wherein W⁵ is independently substitutedwith 0 to 3 R² groups;

W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;

M2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M1a, M1c, and M1d are independently 0 or 1; and

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

In compounds of the invention W⁵ carbocycles and W⁵ heterocycles may beindependently substituted with 0 to 3 R² groups. W⁵ may be a saturated,unsaturated or aromatic ring comprising a mono- or bicyclic carbocycleor heterocycle. W⁵ may have 3 to 10 ring atoms, e.g., 3 to 7 ring atoms.The W⁵ rings are saturated when containing 3 ring atoms, saturated ormono-unsaturated when containing 4 ring atoms, saturated, or mono- ordi-unsaturated when containing 5 ring atoms, and saturated, mono- ordi-unsaturated, or aromatic when containing 6 ring atoms.

A W⁵ heterocycle may be a monocycle having 3 to 7 ring members (2 to 6carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or abicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3heteroatoms selected from N, O, P, and S). W⁵ heterocyclic monocyclesmay have 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 2 heteroatomsselected from N, O, and S); or 5 or 6 ring atoms (3 to 5 carbon atomsand 1 to 2 heteroatoms selected from N and S). W⁵ heterocyclic bicycleshave 7 to 10 ring atoms (6 to 9 carbon atoms and 1 to 2 heteroatomsselected from N, O, and S) arranged as a bicyclo [4,5], [5,5], [5,6], or[6,6] system; or 9 to 10 ring atoms (8 to 9 carbon atoms and 1 to 2hetero atoms selected from N and S) arranged as a bicyclo [5,6] or [6,6]system. The W⁵ heterocycle may be bonded to Y² through a carbon,nitrogen, sulfur or other atom by a stable covalent bond.

W⁵ heterocycles include for example, pyridyl, dihydropyridyl isomers,piperidine, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl,imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl,thiofuranyl, thienyl, and pyrrolyl. W⁵ also includes, but is not limitedto, examples such as:

W⁵ carbocycles and heterocycles may be independently substituted with 0to 3 R² groups, as defined above. For example, substituted W⁵carbocycles include:

Examples of substituted phenyl carbocycles include:

Linking Groups and Linkers

The invention provides conjugates that comprise a compound havingactivity against one or more metabolic diseases that is linked to one ormore phosphonate groups either directly (e.g. through a covalent bond)or through a linking group (i.e. a linker). The nature of the linker isnot critical provided it does not interfere with the ability of thephosphonate containing compound to function as a therapeutic agent. Thephosphonate or the linker can be linked to the compound (e.g. a compoundof 500-523) at any synthetically feasible position on the compound byremoving a hydrogen or any portion of the compound to provide an openvalence for attachment of the phosphonate or the linker.

In one embodiment of the invention the linking group or linker (whichcan be designated “L”) can include all or a portions of the group A⁰,A¹, A², or W³ described herein.

In another embodiment of the invention the linking group or linker has amolecular weight of from about 20 daltons to about 400 daltons.

In another embodiment of the invention the linking group or linker has alength of about 5 angstroms to about 300 angstroms.

In another embodiment of the invention the linking group or linkerseparates the DRUG and a P(═Y¹) residue by about 5 angstroms to about200 angstroms, inclusive, in length.

In another embodiment of the invention the linking group or linker is adivalent, branched or unbranched, saturated or unsaturated, hydrocarbonchain, having from 2 to 25 carbon atoms, wherein one or more (e.g. 1, 2,3, or 4) of the carbon atoms is optionally replaced by (—O—), andwherein the chain is optionally substituted on carbon with one or more(e.g. 1, 2, 3, or 4) substituents selected from (C₁-C₆)alkoxy,(C₃-C₆)cycloalkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkylthio, azido, cyano, nitro, halo,hydroxy, oxo (═O), carboxy, aryl, aryloxy, heteroaryl, andheteroaryloxy.

In another embodiment of the invention the linking group or linker is ofthe formula W-A wherein A is (C₁-C₂₄)alkyl, (C₂-C₂₄)alkenyl,(C₂-C₂₄)alkynyl, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl or a combinationthereof, wherein W is —N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—,—S—, —S(O)—, —S(O)₂—, —N(R)—, —C(═O)—, or a direct bond; wherein each Ris independently H or (C₁-C₆)alkyl.

In another embodiment of the invention the linking group or linker is adivalent radical formed from a peptide.

In another embodiment of the invention the linking group or linker is adivalent radical formed from an amino acid.

In another embodiment of the invention the linking group or linker is adivalent radical formed from poly-L-glutamic acid, poly-L-aspartic acid,poly-L-histidine, poly-L-ornithine, poly-L-serine, poly-L-threonine,poly-L-tyrosine, poly-L-leucine, poly-L-lysine-L-phenylalanine,poly-L-lysine or poly-L-lysine-L-tyrosine.

In another embodiment of the invention the linking group or linker is ofthe formula W—(CH₂)_(n) wherein, n is between about 1 and about 10; andW is —N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—, —S—, —S(O)—,—S(O)₂—, —C(═O)—, —N(R)—, or a direct bond; wherein each R isindependently H or (C₁-C₆)alkyl.

In another embodiment of the invention the linking group or linker ismethylene, ethylene, or propylene.

In another embodiment of the invention the linking group or linker isattached to the phosphonate group through a carbon atom of the linker.

Intracellular Targeting

The phosphonate group of the compounds of the invention may cleave invivo in stages after they have reached the desired site of action, i.e.inside a cell. One mechanism of action inside a cell may entail a firstcleavage, e.g. by esterase, to provide a negatively-charged “locked-in”intermediate. Cleavage of a terminal ester grouping in a compound of theinvention thus affords an unstable intermediate which releases anegatively charged “locked in” intermediate.

After passage inside a cell, intracellular enzymatic cleavage ormodification of the phosphonate or prodrug compound may result in anintracellular accumulation of the cleaved or modified compound by a“trapping” mechanism. The cleaved or modified compound may then be“locked-in” the cell by a significant change in charge, polarity, orother physical property change which decreases the rate at which thecleaved or modified compound can exit the cell, relative to the rate atwhich it entered as the phosphonate prodrug. Other mechanisms by which atherapeutic effect are achieved may be operative as well. Enzymes whichare capable of an enzymatic activation mechanism with the phosphonateprodrug compounds of the invention include, but are not limited to,amidases, esterases, microbial enzymes, phospholipases, cholinesterases,and phosphatases.

From the foregoing, it will be apparent that many different drugs can bederivatized in accord with the present invention. Numerous such drugsare specifically mentioned herein. However, it should be understood thatthe discussion of drug families and their specific members forderivatization according to this invention is not intended to beexhaustive, but merely illustrative.

Compounds for Treating Metabolic Diseases

The compounds of the invention include those that are useful in treatingmetabolic diseases. Metabolic diseases include, but are not limited to,hypercholesterolemia, dyslipidemia, hyperlipoproteinemia, osteoporosis,atherosclerosis, hyperlipedemia, hypolipidemic, hypocholesterolemic,hyperglycaemia, type II diabetes, hypertension, cardiovascular disease,atherosclerosis, eating disorders, anorexia nervosa, obesity and/oranorexia bulimia. In some embodiments, the compounds are useful fortreating diabetes, e.g, type II diabetes, and/or high cholesterol andthose conditions caused by and/or associated with high cholesterol. Thecompounds of the inventions bear one or more (e.g. 1, 2, 3, or 4)phosphonate groups, which may be a prodrug moiety.

The term compounds of the invention include those compounds that areuseful for treating at least one metabolic disease. In particular, thecompounds include Fluvastatin, pitavastatin, ospemifene, AGI-1067,lovastatin, cerivastatin, pravastatin, simvastatin, atorvastatin,sulfonylurea, troglitazone, rosiglitazone, pioglitazone, R-483, MK-767,tesaglitazar, and rosuvastatin.

Typically, compounds of the invention have a molecular weight of fromabout 400 amu to about 10,000 amu; in a specific embodiment of theinvention, compounds have a molecular weight of less than about 5000amu; in another specific embodiment of the invention, compounds have amolecular weight of less than about 2500 amu; in another specificembodiment of the invention, compounds have a molecular weight of lessthan about 1000 amu; in another specific embodiment of the invention,compounds have a molecular weight of less than about 800 amu; in anotherspecific embodiment of the invention, compounds have a molecular weightof less than about 600 amu; and in another specific embodiment of theinvention, compounds have a molecular weight of less than about 600 amuand a molecular weight of greater than about 400 amu.

The compounds of the invention also typically have a logD(polarity) lessthan about 5. In one embodiment the invention provides compounds havinga logD less than about 4; in another one embodiment the inventionprovides compounds having a logD less than about 3; in another oneembodiment the invention provides compounds having a logD greater thanabout −5; in another one embodiment the invention provides compoundshaving a logD greater than about −3; and in another one embodiment theinvention provides compounds having a logD greater than about 0 and lessthan about 3.

Selected substituents within the compounds of the invention are presentto a recursive degree. In this context, “recursive substituent” meansthat a substituent may recite another instance of itself. Because of therecursive nature of such substituents, theoretically, a large number maybe present in any given claim. For example, R^(x) contains a R^(y)substituent. R^(y) can be R², which in turn can be R³. If R³ is selectedto be R^(3c), then a second instance of R^(x) can be selected. One ofordinary skill in the art of medicinal chemistry understands that thetotal number of such substituents is reasonably limited by the desiredproperties of the compound intended. Such properties include, by ofexample and not limitation, physical properties such as molecularweight, solubility or log P, application properties such as activityagainst the intended target, and practical properties such as ease ofsynthesis.

By way of example and not limitation, W³, R^(y) and R³ are all recursivesubstituents in certain claims. Typically, each of these mayindependently occur 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7,6, 5, 4, 3, 2, 1, or 0, times in a given claim. More typically, each ofthese may independently occur 12 or fewer times in a given claim. Moretypically yet, W³ will occur 0 to 8 times, R^(y) will occur 0 to 6 timesand R³ will occur 0 to 10 times in a given claim. Even more typically,W³ will occur 0 to 6 times, R^(y) will occur 0 to 4 times and R³ willoccur 0 to 8 times in a given claim.

Recursive substituents are an intended aspect of the invention. One ofordinary skill in the art of medicinal chemistry understands theversatility of such substituents. To the degree that recursivesubstituents are present in an claim of the invention, the total numberwill be determined as set forth above.

Whenever a compound described herein is substituted with more than oneof the same designated group, e.g., “R¹” or “R^(6a)”, then it will beunderstood that the groups may be the same or different, i.e., eachgroup is independently selected. Wavy lines indicate the site ofcovalent bond attachments to the adjoining groups, moieties, or atoms.

The phosphonate group may be a phosphonate prodrug moiety. The prodrugmoiety may be sensitive to hydrolysis, such as, but not limited to, apivaloyloxymethyl carbonate (POC) or POM group. Alternatively, theprodrug moiety may be sensitive to enzymatic potentiated cleavage, suchas a lactate ester or a phosphonamidate-ester group.

In one embodiment of the invention, the compound is in an isolated andpurified form. Generally, the term “isolated and purified” means thatthe compound is substantially free from biological materials (e.g.blood, tissue, cells, etc.). In one specific embodiment of theinvention, the term means that the compound or conjugate of theinvention is at least about 50 wt. % free from biological materials; inanother specific embodiment, the term means that the compound orconjugate of the invention is at least about 75 wt. % free frombiological materials; in another specific embodiment, the term meansthat the compound or conjugate of the invention is at least about 90 wt.% free from biological materials; in another specific embodiment, theterm means that the compound or conjugate of the invention is at leastabout 98 wt. % free from biological materials; and in anotherembodiment, the term means that the compound or conjugate of theinvention is at least about 99 wt. % free from biological materials. Inanother specific embodiment, the invention provides a compound orconjugate of the invention that has been synthetically prepared (e.g.,ex vivo).

In one embodiment of the invention, the compound is not ananti-inflammatory compound; in another embodiment of the invention thecompound is not an anti-infective; in another embodiment of theinvention the compound is not a compound that is active againstimmune-mediated conditions; in another embodiment of the invention thecompound is not a compound that is not an antimetabolite; in anotherembodiment of the invention the compound is not an antiviral agent; inanother embodiment of the invention the compound is not a nucleoside; inanother embodiment of the invention the compound is not a IMPDHinhibitor; in another embodiment of the invention the compound is not akinase inhibitor; in another embodiment of the invention the compound isnot a PNP inhibitor; in another embodiment of the invention the compoundis a substituted compound of formula 519; in another embodiment of theinvention the compound is not a substituted compound of formula 510; inanother embodiment of the invention the compound is not a compound ofany one of formulae 29-31; in another embodiment of the invention thecompound is not a compound of formula 45.

Cellular Accumulation

In one embodiment, the invention provides compounds capable ofaccumulating in human PBMC (peripheral blood mononuclear cells). PBMCrefer to blood cells having round lymphocytes and monocytes.Physiologically, PBMC are critical components of the mechanism againstinfection. PBMC may be isolated from heparinized whole blood of normalhealthy donors or buffy coats, by standard density gradientcentrifugation and harvested from the interface, washed (e.g.phosphate-buffered saline) and stored in freezing medium. PBMC may becultured in multi-well plates. At various times of culture, supernatantmay be either removed for assessment, or cells may be harvested andanalyzed (Smith R. etal (2003) Blood 102(7):2532-2540). The compounds ofthis claim may further comprise a phosphonate or phosphonate prodrug.More typically, the phosphonate or phosphonate prodrug can have thestructure A³ as described herein.

Typically, compounds of the invention demonstrate improved intracellularhalf-life of the compounds or intracellular metabolites of the compoundsin human PBMC when compared to analogs of the compounds not having thephosphonate or phosphonate prodrug. Typically, the half-life is improvedby at least about 50%, more typically at least in the range 50-100%,still more typically at least about 100%, more typically yet greaterthan about 100%.

In one embodiment of the invention the intracellular half-life of ametabolite of the compound in human PBMCs is improved when compared toan analog of the compound not having the phosphonate or phosphonateprodrug. In such claims, the metabolite may be generatedintracellularly, e.g. generated within human PBMC. The metabolite may bea product of the cleavage of a phosphonate prodrug within human PBMCs.The phosphonate prodrug may be cleaved to form a metabolite having atleast one negative charge at physiological pH. The phosphonate prodrugmay be enzymatically cleaved within human PBMC to form a phosphonatehaving at least one active hydrogen atom of the form P—OH.

Stereoisomers

The compounds of the invention may have chiral centers, e.g., chiralcarbon or phosphorus atoms. The compounds of the invention thus includeracemic mixtures of all stereoisomers, including enantiomers,diastereomers, and atropisomers. In addition, the compounds of theinvention include enriched or resolved optical isomers at any or allasymmetric, chiral atoms. In other words, the chiral centers apparentfrom the depictions are provided as the chiral isomers or racemicmixtures. Both racemic and diastereomeric mixtures, as well as theindividual optical isomers isolated or synthesized, substantially freeof their enantiomeric or diastereomeric partners, are all within thescope of the invention. The racemic mixtures are separated into theirindividual, substantially optically pure isomers through well-knowntechniques such as, for example, the separation of diastereomeric saltsformed with optically active adjuncts, e.g., acids or bases followed byconversion back to the optically active substances. In most instances,the desired optical isomer is synthesized by means of stereospecificreactions, beginning with the appropriate stereoisomer of the desiredstarting material.

The compounds of the invention can also exist as tautomeric isomers incertain cases. All though only one delocalized resonance structure maybe depicted, all such forms are contemplated within the scope of theinvention. For example, ene-amine tautomers can exist for purine,pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and alltheir possible tautomeric forms are within the scope of the invention.

Salts and Hydrates

The compositions of this invention optionally comprise salts of thecompounds herein, especially pharmaceutically acceptable non-toxic saltscontaining, for example, Na⁺, Li⁺, K⁺, Ca⁺² and Mg⁺². Such salts mayinclude those derived by combination of appropriate cations such asalkali and alkaline earth metal ions or ammonium and quaternary aminoions with an acid anion moiety, typically a carboxylic acid. Monovalentsalts are preferred if a water soluble salt is desired.

Metal salts typically are prepared by reacting the metal hydroxide witha compound of this invention. Examples of metal salts which are preparedin this way are salts containing Li⁺, Na⁺, and K⁺. A less soluble metalsalt can be precipitated from the solution of a more soluble salt byaddition of the suitable metal compound.

In addition, salts may be formed from acid addition of certain organicand inorganic acids, e.g., HCl, HBr, H₂SO₄, H₃PO₄ or organic sulfonicacids, to basic centers, typically amines, or to acidic groups. Finally,it is to be understood that the compositions herein comprise compoundsof the invention in their un-ionized, as well as zwitterionic form, andcombinations with stoichiometric amounts of water as in hydrates.

Also included within the scope of this invention are the salts of theparental compounds with one or more amino acids. Any of the amino acidsdescribed above are suitable, especially the naturally-occurring aminoacids found as protein components, although the amino acid typically isone bearing a side chain with a basic or acidic group, e.g., lysine,arginine or glutamic acid, or a neutral group such as glycine, serine,threonine, alanine, isoleucine, or leucine.

Methods of Treating Metabolic Diseases

Another aspect of the invention relates to methods of treating ametabolic disease comprising the step of treating a sample suspected ofexhibiting a phenotype of the disease with a composition of theinvention.

Compositions of the invention may be used to treat metabolic diseases,as intermediates for such compounds or have other utilities as describedbelow. The compositions will bind to locations on the surface or in acavity of a target, e.g., an enzyme, having a unique geometry.Compositions binding may bind with varying degrees of reversibility.Those compounds binding substantially irreversibly are ideal candidatesfor use in this method of the invention. Once labeled, the substantiallyirreversibly binding compositions are useful as probes for the detectionof target involved in and/or associated with the metabolic disease.Accordingly, the invention relates to methods of detecting such bindingin a sample comprising the steps of: treating a sample with acomposition comprising a compound of the invention bound to a label; andobserving the effect of the sample on the activity of the label.Suitable labels are well known in the diagnostics field and includestable free radicals, fluorophores, radioisotopes, enzymes,chemiluminescent groups and chromogens. The compounds herein are labeledin conventional fashion using functional groups such as hydroxyl oramino.

Within the context of the invention samples include natural or man-madematerials such as living organisms; tissue or cell cultures; biologicalsamples such as biological material samples (blood, serum, urine,cerebrospinal fluid, tears, sputum, saliva, tissue samples, and thelike); laboratory samples; food, water, or air samples; bioproductsamples such as extracts of cells, particularly recombinant cellssynthesizing a desired glycoprotein; and the like. Samples can becontained in any medium including water and organic solvent/watermixtures. Samples include living organisms such as humans, and man madematerials such as cell cultures.

The treating step of the invention comprises adding the composition ofthe invention to the sample or it comprises adding a precursor of thecomposition to the sample. The addition step comprises any method ofadministration as described above.

If desired, the activity after application of the composition can beobserved by any method including direct and indirect methods ofdetecting activity, e.g., enzymatic activity. Quantitative, qualitative,and semiquantitative methods of determining such activity are allcontemplated. Typically one of the screening methods described above areapplied, however, any other method such as observation of thephysiological properties of a living organism are also applicable.

Many organisms suffer from metabolic diseases such as diabetes. Thecompounds of this invention are useful in the treatment or prophylaxisof such conditions in animals or in man.

However, in screening compounds it should be kept in mind that theresults of enzyme assays may not correlate with cell culture assays.Thus, a cell based assay should be the primary screening tool.

Screens for Useful Compounds and Compositions

Compositions of the invention are screened for activity by any of theconventional techniques for evaluating enzyme activity. Within thecontext of the invention, typically compositions are first screened invitro and compositions showing appropriate activity are then screenedfor activity in vivo. Compositions having in vitro Ki (inhibitoryconstants) of less then about 5×10⁻⁶ M, typically less than about 1×10⁻⁷M and preferably less than about 5×10⁻⁸ M are preferred for in vivo use.

Useful in vitro screens have been described in detail and will not beelaborated here. However, the examples describe suitable in vitroassays. For example, biological activity of compounds of the inventioncan be assessed by HMG-CoA reductase inhibition (J. Biol. Chem., 269:6810 (1994)). Representative compounds of the invention were found tohave biological activity when measured by this assay.

Pharmaceutical Formulations

The compounds of this invention are formulated with conventionalcarriers and excipients, which will be selected in accord with ordinarypractice. Tablets will contain excipients, glidants, fillers, bindersand the like. Aqueous formulations are prepared in sterile form, andwhen intended for delivery by other than oral administration generallywill be isotonic. All formulations will optionally contain excipientssuch as those set forth in the Handbook of Pharmaceutical Excipients(1986). Excipients include ascorbic acid and other antioxidants,chelating agents such as EDTA, carbohydrates such as dextrin,hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and thelike. The pH of the formulations ranges from about 3 to about 11, but isordinarily about 7 to 10.

While it is possible for the active ingredients to be administered aloneit may be preferable to present them as pharmaceutical formulations. Theformulations, both for veterinary and for human use, of the inventioncomprise at least one active ingredient, as above defined, together withone or more acceptable carriers therefor and optionally othertherapeutic ingredients. The carrier(s) must be “acceptable” in thesense of being compatible with the other ingredients of the formulationand physiologically innocuous to the recipient thereof.

The formulations include those suitable for the foregoing administrationroutes. The formulations may conveniently be presented in unit dosageform and may be prepared by any of the methods well known in the art ofpharmacy. Techniques and formulations generally are found in Remington'sPharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). Such methodsinclude the step of bringing into association the active ingredient withthe carrier which constitutes one or more accessory ingredients. Ingeneral the formulations are prepared by uniformly and intimatelybringing into association the active ingredient with liquid carriers orfinely divided solid carriers or both, and then, if necessary, shapingthe product.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous ornon-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also beadministered as a bolus, electuary or paste.

A tablet is made by compression or molding, optionally with one or moreaccessory ingredients. Compressed tablets may be prepared by compressingin a suitable machine the active ingredient in a free-flowing form suchas a powder or granules, optionally mixed with a binder, lubricant,inert diluent, preservative, surface active or dispersing agent. Moldedtablets may be made by molding in a suitable machine a mixture of thepowdered active ingredient moistened with an inert liquid diluent. Thetablets may optionally be coated or scored and optionally are formulatedso as to provide slow or controlled release of the active ingredienttherefrom.

For administration to the eye or other external tissues e.g., mouth andskin, the formulations are preferably applied as a topical ointment orcream containing the active ingredient(s) in an amount of, for example,0.075 to 20% w/w (including active ingredient(s) in a range between 0.1%and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.),preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w. Whenformulated in an ointment, the active ingredients may be employed witheither a paraffinic or a water-miscible ointment base. Alternatively,the active ingredients may be formulated in a cream with an oil-in-watercream base.

If desired, the aqueous phase of the cream base may include, forexample, at least 30% w/w of a polyhydric alcohol, i.e. an alcoholhaving two or more hydroxyl groups such as propylene glycol, butane1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol(including PEG 400) and mixtures thereof. The topical formulations maydesirably include a compound which enhances absorption or penetration ofthe active ingredient through the skin or other affected areas. Examplesof such dermal penetration enhancers include dimethyl sulphoxide andrelated analogs.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier (otherwise known as an emulgent), it desirablycomprises a mixture of at least one emulsifier with a fat or an oil orwith both a fat and an oil. Preferably, a hydrophilic emulsifier isincluded together with a lipophilic emulsifier which acts as astabilizer. It is also preferred to include both an oil and a fat.Together, the emulsifier(s) with or without stabilizer(s) make up theso-called emulsifying wax, and the wax together with the oil and fatmake up the so-called emulsifying ointment base which forms the oilydispersed phase of the cream formulations.

Emulgents and emulsion stabilizers suitable for use in the formulationof the invention include Tween® 60, Span® 80, cetostearyl alcohol,benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodiumlauryl sulfate.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties. The cream should preferablybe a non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters known asCrodamol CAP may be used, the last three being preferred esters. Thesemay be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils are used.

Pharmaceutical formulations according to the present invention compriseone or more compounds of the invention together with one or morepharmaceutically acceptable carriers or excipients and optionally othertherapeutic agents. Pharmaceutical formulations containing the activeingredient may be in any form suitable for the intended method ofadministration. When used for oral use for example, tablets, troches,lozenges, aqueous or oil suspensions, dispersible powders or granules,emulsions, hard or soft capsules, syrups or elixirs may be prepared.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsincluding sweetening agents, flavoring agents, coloring agents andpreserving agents, in order to provide a palatable preparation. Tabletscontaining the active ingredient in admixture with non-toxicpharmaceutically acceptable excipient which are suitable for manufactureof tablets are acceptable. These excipients may be, for example, inertdiluents, such as calcium or sodium carbonate, lactose, lactosemonohydrate, croscarmellose sodium, povidone, calcium or sodiumphosphate; granulating and disintegrating agents, such as maize starch,or alginic acid; binding agents, such as cellulose, microcrystallinecellulose, starch, gelatin or acacia; and lubricating agents, such asmagnesium stearate, stearic acid or talc. Tablets may be uncoated or maybe coated by known techniques including microencapsulation to delaydisintegration and adsorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearatealone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsuleswhere the active ingredient is mixed with an inert solid diluent, forexample calcium phosphate or kaolin, or as soft gelatin capsules whereinthe active ingredient is mixed with water or an oil medium, such aspeanut oil, liquid paraffin or olive oil.

Aqueous suspensions of the invention contain the active materials inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia,and dispersing or wetting agents such as a naturally occurringphosphatide (e.g., lecithin), a condensation product of an alkyleneoxide with a fatty acid (e.g., polyoxyethylene stearate), a condensationproduct of ethylene oxide with a long chain aliphatic alcohol (e.g.,heptadecaethyleneoxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol anhydride(e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension mayalso contain one or more preservatives such as ethyl or n-propylp-hydroxy-benzoate, one or more coloring agents, one or more flavoringagents and one or more sweetening agents, such as sucrose or saccharin.

Oil suspensions may be formulated by suspending the active ingredient ina vegetable oil, such as arachis oil, olive oil, sesame oil or coconutoil, or in a mineral oil such as liquid paraffin. The oral suspensionsmay contain a thickening agent, such as beeswax, hard paraffin or cetylalcohol. Sweetening agents, such as those set forth above, and flavoringagents may be added to provide a palatable oral preparation. Thesecompositions may be preserved by the addition of an antioxidant such asascorbic acid.

Dispersible powders and granules of the invention suitable forpreparation of an aqueous suspension by the addition of water providethe active ingredient in admixture with a dispersing or wetting agent, asuspending agent, and one or more preservatives. Suitable dispersing orwetting agents and suspending agents are exemplified by those disclosedabove. Additional excipients, for example sweetening, flavoring andcoloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, a mineral oil, such as liquid paraffin, ora mixture of these. Suitable emulsifying agents includenaturally-occurring gums, such as gum acacia and gum tragacanth,naturally occurring phosphatides, such as soybean lecithin, esters orpartial esters derived from fatty acids and hexitol anhydrides, such assorbitan monooleate, and condensation products of these partial esterswith ethylene oxide, such as polyoxyethylene sorbitan monooleate. Theemulsion may also contain sweetening and flavoring agents. Syrups andelixirs may be formulated with sweetening agents, such as glycerol,sorbitol or sucrose. Such formulations may also contain a demulcent, apreservative, a flavoring or a coloring agent.

The pharmaceutical compositions of the invention may be in the form of asterile injectable preparation, such as a sterile injectable aqueous oroleaginous suspension. This suspension may be formulated according tothe known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,such as a solution in 1,3-butane-diol or prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile fixed oils may conventionally be employed as a solventor suspending medium. For this purpose any bland fixed oil may beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid may likewise be used in the preparation ofinjectables.

The amount of active ingredient that may be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans maycontain approximately 1 to 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which may varyfrom about 5 to about 95% of the total compositions (weight:weight). Thepharmaceutical composition can be prepared to provide easily measurableamounts for administration. For example, an aqueous solution intendedfor intravenous infusion may contain from about 3 to 500 μg of theactive ingredient per milliliter of solution in order that infusion of asuitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for administration to the eye include eye dropswherein the active ingredient is dissolved or suspended in a suitablecarrier, especially an aqueous solvent for the active ingredient. Theactive ingredient is preferably present in such formulations in aconcentration of 0.5 to 20%, advantageously 0.5 to 10% particularlyabout 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for intrapulmonary or nasal administration have aparticle size for example in the range of 0.1 to 500 microns (includingparticle sizes in a range between 0.1 and 500 microns in incrementsmicrons such as 0.5, 1, 30 microns, 35 microns, etc.), which isadministered by rapid inhalation through the nasal passage or byinhalation through the mouth so as to reach the alveolar sacs. Suitableformulations include aqueous or oily solutions of the active ingredient.Formulations suitable for aerosol or dry powder administration may beprepared according to conventional methods and may be delivered withother therapeutic agents such as compounds heretofore used in thetreatment or prophylaxis of metabolic diseases as described herein.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

The formulations are presented in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water for injection, immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or an appropriate fraction thereof, of the active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

The invention further provides veterinary compositions comprising atleast one active ingredient as above defined together with a veterinarycarrier therefor.

Veterinary carriers are materials useful for the purpose ofadministering the composition and may be solid, liquid or gaseousmaterials which are otherwise inert or acceptable in the veterinary artand are compatible with the active ingredient. These veterinarycompositions may be administered orally, parenterally or by any otherdesired route.

Compounds of the invention can also be formulated to provide controlledrelease of the active ingredient to allow less frequent dosing or toimprove the pharmacokinetic or toxicity profile of the activeingredient. Accordingly, the invention also provided compositionscomprising one or more compounds of the invention formulated forsustained or controlled release.

Effective dose of active ingredient depends at least on the nature ofthe condition being treated, toxicity, whether the compound is beingused prophylactically (lower doses), the method of delivery, and thepharmaceutical formulation, and will be determined by the clinicianusing conventional dose escalation studies. It can be expected to befrom about 0.0001 to about 100 mg/kg body weight per day. Typically,from about 0.01 to about 10 mg/kg body weight per day. More typically,from about 0.01 to about 5 mg/kg body weight per day. More typically,from about 0.05 to about 0.5 mg/kg body weight per day. For example, thedaily candidate dose for an adult human of approximately 70 kg bodyweight will range from 1 mg to 1000 mg, preferably between 5 mg and 500mg, and may take the form of single or multiple doses.

Routes of Administration

One or more compounds of the invention (herein referred to as the activeingredients) are administered by any route appropriate to the conditionto be treated. Suitable routes include oral, rectal, nasal, topical(including buccal and sublingual), vaginal and parenteral (includingsubcutaneous, intramuscular, intravenous, intradermal, intrathecal andepidural), and the like. It will be appreciated that the preferred routemay vary with for example the condition of the recipient. An advantageof the compounds of this invention is that they are orally bioavailableand can be dosed orally.

Combination Therapy

Active ingredients of the invention are also used in combination withother active ingredients. Such combinations are selected based on thecondition to be treated, cross-reactivities of ingredients andpharmaco-properties of the combination.

It is also possible to combine any compound of the invention with one ormore other active ingredients in a unitary dosage form for simultaneousor sequential administration to a patient. The combination therapy maybe administered as a simultaneous or sequential regimen. Whenadministered sequentially, the combination may be administered in two ormore administrations.

The combination therapy may provide “synergy” and “synergistic effect”,i.e. the effect achieved when the active ingredients used together isgreater than the sum of the effects that results from using thecompounds separately. A synergistic effect may be attained when theactive ingredients are: (1) co-formulated and administered or deliveredsimultaneously in a combined formulation; (2) delivered by alternationor in parallel as separate formulations; or (3) by some other regimen.When delivered in alternation therapy, a synergistic effect may beattained when the compounds are administered or delivered sequentially,e.g., in separate tablets, pills or capsules, or by different injectionsin separate syringes. In general, during alternation therapy, aneffective dosage of each active ingredient is administered sequentially,i.e. serially, whereas in combination therapy, effective dosages of twoor more active ingredients are administered together.

Metabolites of the Compounds of the Invention

Also falling within the scope of this invention are the in vivometabolic products of the compounds described herein. Such products mayresult for example from the oxidation, reduction, hydrolysis, amidation,esterification and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes compoundsproduced by a process comprising contacting a compound of this inventionwith a mammal for a period of time sufficient to yield a metabolicproduct thereof. Such products typically are identified by preparing aradiolabelled (e.g., C¹⁴ or H³) compound of the invention, administeringit parenterally in a detectable dose (e.g., greater than about 0.5mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man,allowing sufficient time for metabolism to occur (typically about 30seconds to 30 hours) and isolating its conversion products from theurine, blood or other biological samples. These products are easilyisolated since they are labeled (others are isolated by the use ofantibodies capable of binding epitopes surviving in the metabolite). Themetabolite structures are determined in conventional fashion, e.g., byMS or NMR analysis. In general, analysis of metabolites is done in thesame way as conventional drug metabolism studies well-known to thoseskilled in the art. The conversion products, so long as they are nototherwise found in vivo, are useful in diagnostic assays for therapeuticdosing of the compounds of the invention even if they possess noeffective activity of their own.

Recipes and methods for determining stability of compounds in surrogategastrointestinal secretions are known. Compounds are defined herein asstable in the gastrointestinal tract where less than about 50 molepercent of the protected groups are deprotected in surrogate intestinalor gastric juice upon incubation for 1 hour at 37° C. Simply because thecompounds are stable to the gastrointestinal tract does not mean thatthey cannot be hydrolyzed in vivo. The phosphonate prodrugs of theinvention typically will be stable in the digestive system but aresubstantially hydrolyzed to the parental drug in the digestive lumen,liver or other metabolic organ, or within cells in general.

Exemplary Methods of Making the Compounds of the Invention.

The invention also relates to methods of making the compositions of theinvention. The compositions are prepared by any of the applicabletechniques of organic synthesis. Many such techniques are well known inthe art. However, many of the known techniques are elaborated inCompendium of Organic Synthetic Methods (John Wiley & Sons, New York),Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T.Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and LeroyWade, 1977; Vol. 4, Leroy G. Wade, jr., 1980; Vol. 5, Leroy G. Wade,Jr., 1984; and Vol. 6, Michael B. Smith; as well as March, J., AdvancedOrganic Chemistry, Third Edition, (John Wiley & Sons, New York, 1985),Comprehensive Organic Synthesis. Selectivity, Strategy & Efficiency inModern Organic Chemistry. In 9 Volumes, Barry M. Trost, Editor-in-Chief(Pergamon Press, New York, 1993 printing).

A number of exemplary methods for the preparation of the compositions ofthe invention are provided below. These methods are intended toillustrate the nature of such preparations are not intended to limit thescope of applicable methods.

Generally, the reaction conditions such as temperature, reaction time,solvents, work-up procedures, and the like, will be those common in theart for the particular reaction to be performed. The cited referencematerial, together with material cited therein, contains detaileddescriptions of such conditions. Typically the temperatures will be−100° C. to 200° C., solvents will be aprotic or protic, and reactiontimes will be 10 seconds to 10 days. Work-up typically consists ofquenching any unreacted reagents followed by partition between awater/organic layer system (extraction) and separating the layercontaining the product.

Oxidation and reduction reactions are typically carried out attemperatures near room temperature (about 20° C.), although for metalhydride reductions frequently the temperature is reduced to 0° C. to−100° C., solvents are typically aprotic for reductions and may beeither protic or aprotic for oxidations. Reaction times are adjusted toachieve desired conversions.

Condensation reactions are typically carried out at temperatures nearroom temperature, although for non-equilibrating, kinetically controlledcondensations reduced temperatures (0° C. to −100° C.) are also common.Solvents can be either protic (common in equilibrating reactions) oraprotic (common in kinetically controlled reactions).

Standard synthetic techniques such as azeotropic removal of reactionby-products and use of anhydrous reaction conditions (e.g., inert gasenvironments) are common in the art and will be applied when applicable.

SCHEMES AND EXAMPLES

General aspects of these exemplary methods are described below and inthe Examples. Each of the products of the following processes isoptionally separated, isolated, and/or purified prior to its use insubsequent processes.

Generally, the reaction conditions such as temperature, reaction time,solvents, work-up procedures, and the like, will be those common in theart for the particular reaction to be performed. The cited referencematerial, together with material cited therein, contains detaileddescriptions of such conditions. Typically the temperatures will be−100° C. to 200° C., solvents will be aprotic or protic, and reactiontimes will be 10 seconds to 10 days. Work-up typically consists ofquenching any unreacted reagents followed by partition between awater/organic layer system (extraction) and separating the layercontaining the product.

Oxidation and reduction reactions are typically carried out attemperatures near room temperature (about 20° C.), although for metalhydride reductions frequently the temperature is reduced to 0° C. to−100° C., solvents are typically aprotic for reductions and may beeither protic or aprotic for oxidations. Reaction times are adjusted toachieve desired conversions.

Condensation reactions are typically carried out at temperatures nearroom temperature, although for non-equilibrating, kinetically controlledcondensations reduced temperatures (0° C. to −100° C.) are also common.Solvents can be either protic (common in equilibrating reactions) oraprotic (common in kinetically controlled reactions).

Standard synthetic techniques such as azeotropic removal of reactionby-products and use of anhydrous reaction conditions (e.g., inert gasenvironments) are common in the art and will be applied when applicable.

The terms “treated”, “treating”, “treatment”, and the like, when used inconnection with a chemical synthetic operation, mean contacting, mixing,reacting, allowing to react, bringing into contact, and other termscommon in the art for indicating that one or more chemical entities istreated in such a manner as to convert it to one or more other chemicalentities. This means that “treating compound one with compound two” issynonymous with “allowing compound one to react with compound two”,“contacting compound one with compound two”, “reacting compound one withcompound two”, and other expressions common in the art of organicsynthesis for reasonably indicating that compound one was “treated”,“reacted”, “allowed to react”, etc., with compound two. For example,treating indicates the reasonable and usual manner in which organicchemicals are allowed to react. Normal concentrations (0.01M to 10M,typically 0.1M to 1M), temperatures (−100° C. to 250° C., typically −78°C. to 150° C., more typically −78° C. to 100° C., still more typically0° C. to 100° C.), reaction vessels (typically glass, plastic, metal),solvents, pressures, atmospheres (typically air for oxygen and waterinsensitive reactions or nitrogen or argon for oxygen or watersensitive), etc., are intended unless otherwise indicated. The knowledgeof similar reactions known in the art of organic synthesis are used inselecting the conditions and apparatus for “treating” in a givenprocess. In particular, one of ordinary skill in the art of organicsynthesis selects conditions and apparatus reasonably expected tosuccessfully carry out the chemical reactions of the described processesbased on the knowledge in the art.

Modifications of each of the exemplary schemes and in the examples(hereafter “exemplary schemes”) leads to various analogs of the specificexemplary materials produce. The above-cited citations describingsuitable methods of organic synthesis are applicable to suchmodifications.

In each of the exemplary schemes it may be advantageous to separatereaction products from one another and/or from starting materials. Thedesired products of each step or series of steps is separated and/orpurified (hereinafter separated) to the desired degree of homogeneity bythe techniques common in the art. Typically such separations involvemultiphase extraction, crystallization from a solvent or solventmixture, distillation, sublimation, or chromatography. Chromatographycan involve any number of methods including, for example: reverse-phaseand normal phase; size exclusion; ion exchange; high, medium, and lowpressure liquid chromatography methods and apparatus; small scaleanalytical; simulated moving bed (SMB) and preparative thin or thicklayer chromatography, as well as techniques of small scale thin layerand flash chromatography.

Another class of separation methods involves treatment of a mixture witha reagent selected to bind to or render otherwise separable a desiredproduct, unreacted starting material, reaction by product, or the like.Such reagents include adsorbents or absorbents such as activated carbon,molecular sieves, ion exchange media, or the like. Alternatively, thereagents can be acids in the case of a basic material, bases in the caseof an acidic material, binding reagents such as antibodies, bindingproteins, selective chelators such as crown ethers, liquid/liquid ionextraction reagents (LIX), or the like.

Selection of appropriate methods of separation depends on the nature ofthe materials involved. For example, boiling point, and molecular weightin distillation and sublimation, presence or absence of polar functionalgroups in chromatography, stability of materials in acidic and basicmedia in multiphase extraction, and the like. One skilled in the artwill apply techniques most likely to achieve the desired separation.

A single stereoisomer, e.g., an enantiomer, substantially free of itsstereoisomer may be obtained by resolution of the racemic mixture usinga method such as formation of diastereomers using optically activeresolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L.Eliel, McGraw Hill; Lochmuller, C. H., (1975) J Chromatogr., 113:(3)283-302). Racemic mixtures of chiral compounds of the invention can beseparated and isolated by any suitable method, including: (1) formationof ionic, diastereomeric salts with chiral compounds and separation byfractional crystallization or other methods, (2) formation ofdiastereomeric compounds with chiral derivatizing reagents, separationof the diastereomers, and conversion to the pure stereoisomers, and (3)separation of the substantially pure or enriched stereoisomers directlyunder chiral conditions.

Under method (1), diastereomeric salts can be formed by reaction ofenantiomerically pure chiral bases such as brucine, quinine, ephedrine,strychnine, α-methyl-β-phenylethylamine (amphetamine), and the like withasymmetric compounds bearing acidic functionality, such as carboxylicacid and sulfonic acid. The diastereomeric salts may be induced toseparate by fractional crystallization or ionic chromatography. Forseparation of the optical isomers of amino compounds, addition of chiralcarboxylic or sulfonic acids, such as camphorsulfonic acid, tartaricacid, mandelic acid, or lactic acid can result in formation of thediastereomeric salts.

Alternatively, by method (2), the substrate to be resolved is reactedwith one enantiomer of a chiral compound to form a diastereomeric pair(Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds,John Wiley & Sons, Inc., p. 322). Diastereomeric compounds can be formedby reacting asymmetric compounds with enantiomerically pure chiralderivatizing reagents, such as menthyl derivatives, followed byseparation of the diastereomers and hydrolysis to yield the free,enantiomerically enriched xanthene. A method of determining opticalpurity involves making chiral esters, such as a menthyl ester, e.g., (−)menthyl chloroformate in the presence of base, or Mosher ester,α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org.Chem. 47:4165), of the racemic mixture, and analyzing the NMR spectrumfor the presence of the two atropisomeric diastereomers. Stablediastereomers of atropisomeric compounds can be separated and isolatedby normal- and reverse-phase chromatography following methods forseparation of atropisomeric naphthyl-isoquinolines (Hoye, T., WO96/15111). By method (3), a racemic mixture of two enantiomers can beseparated by chromatography using a chiral stationary phase (ChiralLiquid Chromatography (1989) W. J. Lough, Ed. Chapman and Hall, NewYork; Okamoto, (1990) J. of Chromatogr. 513:375-378). Enriched orpurified enantiomers can be distinguished by methods used to distinguishother chiral molecules with asymmetric carbon atoms, such as opticalrotation and circular dichroism.

Examples General Section

A number of exemplary methods for the preparation of compounds of theinvention are provided herein, for example, in the Examples hereinbelow.These methods are intended to illustrate the nature of such preparationsare not intended to limit the scope of applicable methods. Certaincompounds of the invention can be used as intermediates for thepreparation of other compounds of the invention. For example, theinterconversion of various phosphonate compounds of the invention isillustrated below.

Interconversions of the Phosphonates R-LINK-P(O)(OR¹)₂,R-LINK-P(O)(OR¹)(OH) AND R-LINK-P(O)(OH)₂.

The following schemes 32-38 described the preparation of phosphonateesters of the general structure R-link-P(O)(OR¹)₂, in which the groupsR¹ may be the same or different. The R¹ groups attached to a phosphonateester, or to precursors thereto, may be changed using establishedchemical transformations. The interconversion reactions of phosphonatesare illustrated in Scheme S32. The group R in Scheme 32 represents thesubstructure, i.e. the drug “scaffold, to which the substituentlink-P(O)(OR¹)₂ is attached, either in the compounds of the invention,or in precursors thereto. At the point in the synthetic route ofconducting a phosphonate interconversion, certain functional groups in Rmay be protected. The methods employed for a given phosphonatetransformation depend on the nature of the substituent R¹, and of thesubstrate to which the phosphonate group is attached. The preparationand hydrolysis of phosphonate esters is described in Organic PhosphorusCompounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976, p. 9ff.

In general, synthesis of phosphonate esters is achieved by coupling anucleophile amine or alcohol with the corresponding activatedphosphonate electrophilic precursor. For example, chlorophosphonateaddition on to 5′-hydroxy of nucleoside is a well known method forpreparation of nucleoside phosphate monoesters. The activated precursorcan be prepared by several well known methods. Chlorophosphonates usefulfor synthesis of the prodrugs are prepared from thesubstituted-1,3-propanediol (Wissner, et al, (1992) J. Med. Chem.35:1650). Chlorophosphonates are made by oxidation of the correspondingchlorophospholanes (Anderson, et al, (1984) J. Org. Chem. 49:1304) whichare obtained by reaction of the substituted diol with phosphorustrichloride. Alternatively, the chlorophosphonate agent is made bytreating substituted-1,3-diols with phosphorusoxychloride (Patois, etal, (1990) J. Chem. Soc. Perkin Trans. I, 1577). Chlorophosphonatespecies may also be generated in situ from corresponding cyclicphosphites (Silverburg, et al., (1996) Tetrahedron lett., 37:771-774),which in turn can be either made from chlorophospholane orphosphoramidate intermediate. Phosphoroflouridate intermediate preparedeither from pyrophosphate or phosphoric acid may also act as precursorin preparation of cyclic prodrugs (Watanabe et al., (1988) Tetrahedronlett., 29:5763-66).

Phosphonate prodrugs of the present invention may also be prepared fromthe free acid by Mitsunobu reactions (Mitsunobu, (1981) Synthesis, 1;Campbell, (1992) J. Org. Chem. 57:6331), and other acid couplingreagents including, but not limited to, carbodiimides (Alexander, et al,(1994) Collect. Czech. Chem. Commun. 59:1853; Casara et al, (1992)Bioorg. Med. Chem. Lett. 2:145; Ohashi et al, (1988) Tetrahedron Lett.,29:1189), and benzotriazolyloxytris-(dimethylamino)phosphonium salts(Campagne et al (1993) Tetrahedron Lett. 34:6743).

Aryl halides undergo Ni⁺² catalyzed reaction with phosphite derivativesto give aryl phosphonate containing compounds (Balthazar, et al (1980)J. Org. Chem. 45:5425). Phosphonates may also be prepared from thechlorophosphonate in the presence of a palladium catalyst using aromatictriflates (Petrakis et al (1987) J. Am. Chem. Soc. 109:2831; Lu et al(1987) Synthesis 726). In another method, aryl phosphonate esters areprepared from aryl phosphates under anionic rearrangement conditions(Melvin (1981) Tetrahedron Lett. 22:3375; Casteel et al (1991)Synthesis, 691). N-Alkoxy aryl salts with alkali met al derivatives ofcyclic alkyl phosphonate provide general synthesis forheteroaryl-2-phosphonate linkers (Redmore (1970) J. Org. Chem. 35:4114).These above mentioned methods can also be extended to compounds wherethe W⁵ group is a heterocycle. Cyclic-1,3-propanyl prodrugs ofphosphonates are also synthesized from phosphonic diacids andsubstituted propane-1,3-diols using a coupling reagent such as1,3-dicyclohexylcarbodiimide (DCC) in presence of a base (e.g.,pyridine). Other carbodiimide based coupling agents like1,3-disopropylcarbodiimide or water soluble reagent,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) canalso be utilized for the synthesis of cyclic phosphonate prodrugs.

The conversion of a phosphonate diester S32.1 into the correspondingphosphonate monoester S32.2 (Scheme 32, Reaction 1) is accomplished by anumber of methods. For example, the ester S32.1 in which R¹ is anaralkyl group such as benzyl, is converted into the monoester compoundS32.2 by reaction with a tertiary organic base such asdiazabicyclooctane (DABCO) or quinuclidine, as described in J. Org.Chem. (1995) 60:2946. The reaction is performed in an inert hydrocarbonsolvent such as toluene or xylene, at about 110° C. The conversion ofthe diester S32.1 in which R¹ is an aryl group such as phenyl, or analkenyl group such as allyl, into the monoester S32.2 is effected bytreatment of the ester S32.1 with a base such as aqueous sodiumhydroxide in acetonitrile or lithium hydroxide in aqueoustetrahydrofuran. Phosphonate diesters S32.1 in which one of the groupsR¹ is aralkyl, such as benzyl, and the other is alkyl, is converted intothe monoesters S32.2 in which R¹ is alkyl by hydrogenation, for exampleusing a palladium on carbon catalyst. Phosphonate diesters in which bothof the groups R¹ are alkenyl, such as allyl, is converted into themonoester S32.2 in which R¹ is alkenyl, by treatment withchlorotris(triphenylphosphine)rhodium (Wilkinson's catalyst) in aqueousethanol at reflux, optionally in the presence of diazabicyclooctane, forexample by using the procedure described in J. Org. Chem. (1973)38:3224, for the cleavage of allyl carboxylates.

The conversion of a phosphonate diester S32.1 or a phosphonate monoesterS32.2 into the corresponding phosphonic acid S32.3 (Scheme 32, Reactions2 and 3) can be effected by reaction of the diester or the monoesterwith trimethylsilyl bromide, as described in J. Chem. Soc., Chem. Comm.,(1979) 739. The reaction is conducted in an inert solvent such as, forexample, dichloromethane, optionally in the presence of a silylatingagent such as bis(trimethylsilyl)trifluoroacetamide, at ambienttemperature. A phosphonate monoester S32.2 in which R¹ is aralkyl suchas benzyl, is converted into the corresponding phosphonic acid S32.3 byhydrogenation over a palladium catalyst, or by treatment with hydrogenchloride in an ethereal solvent such as dioxane. A phosphonate monoesterS32.2 in which R¹ is alkenyl such as, for example, allyl, is convertedinto the phosphonic acid S32.3 by reaction with Wilkinson's catalyst inan aqueous organic solvent, for example in 15% aqueous acetonitrile, orin aqueous ethanol, for example using the procedure described in Helv.Chim. Acta. (1985) 68:618. Palladium catalyzed hydrogenolysis ofphosphonate esters S32.1 in which R¹ is benzyl is described in J. Org.Chem. (1959) 24:434. Platinum-catalyzed hydrogenolysis of phosphonateesters S32.1 in which R¹ is phenyl is described in J. Am. Chem. Soc.(1956) 78:2336.

The conversion of a phosphonate mono ester S32.2 into a phosphonatediester S32.1 (Scheme 32, Reaction 4) in which the newly introduced R¹group is alkyl, aralkyl, haloalkyl such as chloroethyl, or aralkyl iseffected by a number of reactions in which the substrate S32.2 isreacted with a hydroxy compound R¹OH, in the presence of a couplingagent. Typically, the second phosphonate ester group is different thanthe first introduced phosphonate ester group, i.e. R¹ is followed by theintroduction of R² where each of R¹ and R² is alkyl, aralkyl, haloalkylsuch as chloroethyl, or aralkyl (Scheme 32, Reaction 4a) whereby S32.2is converted to S32.1a. Suitable coupling agents are those employed forthe preparation of carboxylate esters, and include a carbodiimide suchas dicyclohexylcarbodiimide, in which case the reaction is preferablyconducted in a basic organic solvent such as pyridine, or(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(PYBOP, Sigma), in which case the reaction is performed in a polarsolvent such as dimethylformamide, in the presence of a tertiary organicbase such as diisopropylethylamine, or Aldrithiol-2 (Aldrich) in whichcase the reaction is conducted in a basic solvent such as pyridine, inthe presence of a triaryl phosphine such as triphenylphosphine.Alternatively, the conversion of the phosphonate monoester S32.2 to thediester S32.1 is effected by the use of the Mitsunobu reaction, asdescribed above. The substrate is reacted with the hydroxy compoundR¹OH, in the presence of diethyl azodicarboxylate and a triarylphosphinesuch as triphenyl phosphine. Alternatively, the phosphonate monoesterS32.2 is transformed into the phosphonate diester S32.1, in which theintroduced R¹ group is alkenyl or aralkyl, by reaction of the monoesterwith the halide R¹Br, in which R¹ is as alkenyl or aralkyl. Thealkylation reaction is conducted in a polar organic solvent such asdimethylformamide or acetonitrile, in the presence of a base such ascesium carbonate. Alternatively, the phosphonate monoester istransformed into the phosphonate diester in a two step procedure. In thefirst step, the phosphonate monoester S32.2 is transformed into thechloro analog RP(O)(OR¹)Cl by reaction with thionyl chloride or oxalylchloride and the like, as described in Organic Phosphorus Compounds, G.M. Kosolapoff, L. Maeir, eds, Wiley, 1976, p. 17, and the thus-obtainedproduct RP(O)(OR¹)Cl is then reacted with the hydroxy compound R¹OH, inthe presence of a base such as triethylamine, to afford the phosphonatediester S32.1.

A phosphonic acid R-link-P(O)(OH)₂ is transformed into a phosphonatemonoester RP(O)(OR¹)(OH) (Scheme 32, Reaction 5) by means of the methodsdescribed above of for the preparation of the phosphonate diesterR-link-P(O)(OR¹)₂ S32.1, except that only one molar proportion of thecomponent R¹OH or R¹Br is employed. Dialkyl phosphonates may be preparedaccording to the methods of: Quast et al (1974) Synthesis 490; Stowellet al (1990) Tetrahedron Lett. 3261;U.S. Pat. No. 5,663,159.

A phosphonic acid R-link-P(O)(OH)₂ S32.3 is transformed into aphosphonate diester R-link-P(O)(OR¹)₂ S32.1 (Scheme 32, Reaction 6) by acoupling reaction with the hydroxy compound R¹OH, in the presence of acoupling agent such as Aldrithiol-2 (Aldrich) and triphenylphosphine.The reaction is conducted in a basic solvent such as pyridine.Alternatively, phosphonic acids S32.3 are transformed into phosphonicesters S32.1 in which R¹ is aryl, by means of a coupling reactionemploying, for example, dicyclohexylcarbodiimide in pyridine at ca 70°C. Alternatively, phosphonic acids S32.3 are transformed into phosphonicesters S32.1 in which R¹ is alkenyl, by means of an alkylation reaction.The phosphonic acid is reacted with the alkenyl bromide R¹Br in a polarorganic solvent such as acetonitrile solution at reflux temperature, thepresence of a base such as cesium carbonate, to afford the phosphonicester S32.1.

Preparation of Phosphonate Carbamates.

Phosphonate esters may contain a carbamate linkage. The preparation ofcarbamates is described in Comprehensive Organic Functional GroupTransformations, A. R. Katritzky, ed., Pergamon, 1995, Vol. 6, p. 416ff,and in Organic Functional Group Preparations, by S. R. Sandler and W.Karo, Academic Press, 1986, p. 260ff. The carbamoyl group may be formedby reaction of a hydroxy group according to the methods known in theart, including the teachings of Ellis, US 2002/0103378 A1 and Hajima,U.S. 6018049.

Scheme 33 illustrates various methods by which the carbamate linkage issynthesized. As shown in Scheme 33, in the general reaction generatingcarbamates, an alcohol S33.1, is converted into the activated derivativeS33.2 in which Lv is a leaving group such as halo, imidazolyl,benztriazolyl and the like, as described herein. The activatedderivative S33.2 is then reacted with an amine S33.3, to afford thecarbamate product S33.4. Examples 1-7 in Scheme 33 depict methods bywhich the general reaction is effected. Examples 8-10 illustratealternative methods for the preparation of carbamates.

Scheme 33, Example 1 illustrates the preparation of carbamates employinga chloroformyl derivative of the alcohol S33.5. In this procedure, thealcohol S33.5 is reacted with phosgene, in an inert solvent such astoluene, at about 0° C., as described in Org. Syn. Coll. Vol. 3, 167,1965, or with an equivalent reagent such as trichloromethoxychloroformate, as described in Org. Syn. Coll. Vol. 6, 715, 1988, toafford the chloroformate S33.6. The latter compound is then reacted withthe amine component S33.3, in the presence of an organic or inorganicbase, to afford the carbamate S33.7. For example, the chloroformylcompound S33.6 is reacted with the amine S33.3 in a water-misciblesolvent such as tetrahydrofuran, in the presence of aqueous sodiumhydroxide, as described in Org. Syn. Coll. Vol. 3, 167, 1965, to yieldthe carbamate S33.7. Alternatively, the reaction is performed indichloromethane in the presence of an organic base such asdiisopropylethylamine or dimethylaminopyridine.

Scheme 33, Example 2 depicts the reaction of the chloroformate compoundS33.6 with imidazole to produce the imidazolide S33.8. The imidazolideproduct is then reacted with the amine S33.3 to yield the carbamateS33.7. The preparation of the imidazolide is performed in an aproticsolvent such as dichloromethane at 0°, and the preparation of thecarbamate is conducted in a similar solvent at ambient temperature,optionally in the presence of a base such as dimethylaminopyridine, asdescribed in J. Med. Chem., 1989, 32, 357.

Scheme 33 Example 3, depicts the reaction of the chloroformate S33.6with an activated hydroxyl compound R″OH, to yield the mixed carbonateester S33.10. The reaction is conducted in an inert organic solvent suchas ether or dichloromethane, in the presence of a base such asdicyclohexylamine or triethylamine. The hydroxyl component R″OH isselected from the group of compounds S33.19-S33.24 shown in Scheme 33,and similar compounds. For example, if the component R″OH ishydroxybenztriazole S33.19, N-hydroxysuccinimide S33.20, orpentachlorophenol, S33.21, the mixed carbonate S33.10 is obtained by thereaction of the chloroformate with the hydroxyl compound in an etherealsolvent in the presence of dicyclohexylamine, as described in Can. J.Chem., 1982, 60, 976. A similar reaction in which the component R″OH ispentafluorophenol S33.22 or 2-hydroxypyridine S33.23 is performed in anethereal solvent in the presence of triethylamine, as described in Syn.,1986, 303, and Chem. Ber. 118, 468, 1985.

Scheme 33 Example 4 illustrates the preparation of carbamates in whichan alkyloxycarbonylimidazole S33.8 is employed. In this procedure, analcohol S33.5 is reacted with an equimolar amount of carbonyldiimidazole S33.11 to prepare the intermediate S33.8. The reaction isconducted in an aprotic organic solvent such as dichloromethane ortetrahydrofuran. The acyloxyimidazole S33.8 is then reacted with anequimolar amount of the amine R′NH₂ to afford the carbamate S33.7. Thereaction is performed in an aprotic organic solvent such asdichloromethane, as described in Tet. Lett., 42, 2001, 5227, to affordthe carbamate S33.7.

Scheme 33, Example 5 illustrates the preparation of carbamates by meansof an intermediate alkoxycarbonylbenztriazole S33.13. In this procedure,an alcohol ROH is reacted at ambient temperature with an equimolaramount of benztriazole carbonyl chloride S33.12, to afford thealkoxycarbonyl product S33.13. The reaction is performed in an organicsolvent such as benzene or toluene, in the presence of a tertiaryorganic amine such as triethylamine, as described in Synthesis., 1977,704. The product is then reacted with the amine R′NH₂ to afford thecarbamate S33.7. The reaction is conducted in toluene or ethanol, atfrom ambient temperature to about 80° C. as described in Synthesis.,1977, 704.

Scheme 33, Example 6 illustrates the preparation of carbamates in whicha carbonate (R′O)₂CO, S33.14, is reacted with an alcohol S33.5 to affordthe intermediate alkyloxycarbonyl intermediate S33.15. The latterreagent is then reacted with the amine R′NH₂ to afford the carbamateS33.7. The procedure in which the reagent S33.15 is derived fromhydroxybenztriazole S33.19 is described in Synthesis, 1993, 908; theprocedure in which the reagent S33.15 is derived fromN-hydroxysuccinimide S33.20 is described in Tet. Lett., 1992, 2781; theprocedure in which the reagent S33.15 is derived from 2-hydroxypyridineS33.23 is described in Tet. Lett., 1991, 4251; the procedure in whichthe reagent S33.15 is derived from 4-nitrophenol S33.24 is described inSynthesis. 1993, 103. The reaction between equimolar amounts of thealcohol ROH and the carbonate S33.14 is conducted in an inert organicsolvent at ambient temperature.

Scheme 33, Example 7 illustrates the preparation of carbamates fromalkoxycarbonyl azides S33.16. In this procedure, an alkyl chloroformateS33.6 is reacted with an azide, for example sodium azide, to afford thealkoxycarbonyl azide S33.16. The latter compound is then reacted with anequimolar amount of the amine R′NH₂ to afford the carbamate S33.7. Thereaction is conducted at ambient temperature in a polar aprotic solventsuch as dimethylsulfoxide, for example as described in Synthesis., 1982,404.

Scheme 33, Example 8 illustrates the preparation of carbamates by meansof the reaction between an alcohol ROH and the chloroformyl derivativeof an amine S33.17. In this procedure, which is described in SyntheticOrganic Chemistry, R. B. Wagner, H. D. Zook, Wiley, 1953, p. 647, thereactants are combined at ambient temperature in an aprotic solvent suchas acetonitrile, in the presence of a base such as triethylamine, toafford the carbamate S33.7.

Scheme 33, Example 9 illustrates the preparation of carbamates by meansof the reaction between an alcohol ROH and an isocyanate S33.18. In thisprocedure, which is described in Synthetic Organic Chemistry, R. B.Wagner, H. D. Zook, Wiley, 1953, p. 645, the reactants are combined atambient temperature in an aprotic solvent such as ether ordichloromethane and the like, to afford the carbamate S33.7.

Scheme 33, Example 10 illustrates the preparation of carbamates by meansof the reaction between an alcohol ROH and an amine R′NH₂. In thisprocedure, which is described in Chem. Lett. 1972, 373, the reactantsare combined at ambient temperature in an aprotic organic solvent suchas tetrahydrofuran, in the presence of a tertiary base such astriethylamine, and selenium. Carbon monoxide is passed through thesolution and the reaction proceeds to afford the carbamate S33.7.

Preparation of Carboalkoxy-Substituted Phosphonate Bisamidates,Monoamidates, Diesters and Monoesters.

A number of methods are available for the conversion of phosphonic acidsinto amidates and esters. In one group of methods, the phosphonic acidis either converted into an isolated activated intermediate such as aphosphoryl chloride, or the phosphonic acid is activated in situ forreaction with an amine or a hydroxy compound.

The conversion of phosphonic acids into phosphoryl chlorides isaccomplished by reaction with thionyl chloride, for example as describedin J. Gen. Chem. USSR, 1983, 53, 480, Zh. ObscheiKhim., 1958, 28, 1063,or J. Org. Chem., 1994, 59, 6144, or by reaction with oxalyl chloride,as described in J. Am. Chem. Soc., 1994, 116, 3251, or J. Org. Chem.,1994, 59, 6144, or by reaction with phosphorus pentachloride, asdescribed in J. Org. Chem., 2001, 66, 329, or in J. Med. Chem., 1995,38, 1372. The resultant phosphoryl chlorides are then reacted withamines or hydroxy compounds in the presence of a base to afford theamidate or ester products.

Phosphonic acids are converted into activated imidazolyl derivatives byreaction with carbonyl diimidazole, as described in J. Chem. Soc., Chem.Comm. (1991) 312, or Nucleosides & Nucleotides (2000) 19:1885. Activatedsulfonyloxy derivatives are obtained by the reaction of phosphonic acidswith trichloromethylsulfonyl chloride or withtriisopropylbenzenesulfonyl chloride, as described in Tet. Lett. (1996)7857, or Bioorg. Med. Chem. Lett. (1998) 8:663. The activatedsulfonyloxy derivatives are then reacted with amines or hydroxycompounds to afford amidates or esters.

Alternatively, the phosphonic acid and the amine or hydroxy reactant arecombined in the presence of a diimide coupling agent. The preparation ofphosphonic amidates and esters by means of coupling reactions in thepresence of dicyclohexyl carbodiimide is described, for example, in J.Chem. Soc., Chem. Comm. (1991) 312 or Coll. Czech. Chem. Comm. (1987)52:2792. The use of ethyl dimethylaminopropyl carbodiimide foractivation and coupling of phosphonic acids is described in Tet. Lett.,(2001) 42:8841, or Nucleosides & Nucleotides (2000) 19:1885.

A number of additional coupling reagents have been described for thepreparation of amidates and esters from phosphonic acids. The agentsinclude Aldrithiol-2, and PYBOP and BOP, as described in J. Org. Chem.,1995, 60, 5214, and J. Med. Chem. (1997) 40:3842,mesitylene-2-sulfonyl-3-nitro-1,2,4-triazole (MSNT), as described in J.Med. Chem. (1996) 39:4958, diphenylphosphoryl azide, as described in J.Org. Chem. (1984) 49:1158,1-(2,4,6-triisopropylbenzenesulfonyl-3-nitro-1,2,4-triazole (TPSNT) asdescribed in Bioorg. Med. Chem. Lett. (1998) 8:1013,bromotris(dimethylamino)phosphonium hexafluorophosphate (BroP), asdescribed in Tet. Lett., (1996) 37:3997,2-chloro-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphinane, as described inNucleosides Nucleotides 1995, 14, 871, and diphenyl chlorophosphate, asdescribed in J. Med. Chem., 1988, 31, 1305.

Phosphonic acids are converted into amidates and esters by means of theMitsunobu reaction, in which the phosphonic acid and the amine orhydroxy reactant are combined in the presence of a triaryl phosphine anda dialkyl azodicarboxylate. The procedure is described in Org. Lett.,2001, 3, 643, or J. Med. Chem., 1997, 40, 3842.

Phosphonic esters are also obtained by the reaction between phosphonicacids and halo compounds, in the presence of a suitable base. The methodis described, for example, in Anal. Chem., 1987, 59, 1056, or J. Chem.Soc. Perkin Trans., I, 1993, 19, 2303, or J. Med. Chem., 1995, 38, 1372,or Tet. Lett., 2002, 43, 1161.

Schemes 34-37 illustrate the conversion of phosphonate esters andphosphonic acids into carboalkoxy-substituted phosphonbisamidates(Scheme 34), phosphonamidates (Scheme 35), phosphonate monoesters(Scheme 36) and phosphonate diesters, (Scheme 37). Scheme 38 illustratessynthesis of gem-dialkyl amino phosphonate reagents.

Scheme 34 illustrates various methods for the conversion of phosphonatediesters S34.1 into phosphonbisamidates S34.5. The diester S34.1,prepared as described previously, is hydrolyzed, either to the monoesterS34.2 or to the phosphonic acid S34.6. The methods employed for thesetransformations are described above. The monoester S34.2 is convertedinto the monoamidate S34.3 by reaction with an aminoester S34.9, inwhich the group R² is H or alkyl; the group R^(4b) is a divalentalkylene moiety such as, for example, CHCH₃, CHCH₂CH₃, CH(CH(CH₃)₂),CH(CH₂Ph), and the like, or a side chain group present in natural ormodified aminoacids; and the group R^(5b) is C₁-C₁₂ alkyl, such asmethyl, ethyl, propyl, isopropyl, or isobutyl; C₆-C₂₀ aryl, such asphenyl or substituted phenyl; or C₆-C₂₀ arylalkyl, such as benzyl orbenzyhydryl. The reactants are combined in the presence of a couplingagent such as a carbodiimide, for example dicyclohexyl carbodiimide, asdescribed in J. Am. Chem. Soc., (1957) 79:3575, optionally in thepresence of an activating agent such as hydroxybenztriazole, to yieldthe amidate product S34.3. The amidate-forming reaction is also effectedin the presence of coupling agents such as BOP, as described in J. Org.Chem. (1995) 60:5214, Aldrithiol, PYBOP and similar coupling agents usedfor the preparation of amides and esters. Alternatively, the reactantsS34.2 and S34.9 are transformed into the monoamidate S34.3 by means of aMitsunobu reaction. The preparation of amidates by means of theMitsunobu reaction is described in J. Med. Chem. (1995) 38:2742.Equimolar amounts of the reactants are combined in an inert solvent suchas tetrahydrofuran in the presence of a triaryl phosphine and a dialkylazodicarboxylate. The thus-obtained monoamidate ester S34.3 is thentransformed into amidate phosphonic acid S34.4. The conditions used forthe hydrolysis reaction depend on the nature of the R¹ group, asdescribed previously. The phosphonic acid amidate S34.4 is then reactedwith an aminoester S34.9, as described above, to yield the bisamidateproduct S34.5, in which the amino substituents are the same ordifferent. Alternatively, the phosphonic acid S34.6 may be treated withtwo different amino ester reagents simulataneously, i.e. S34.9 where R²,R^(4b) or R^(5b) are different. The resulting mixture of bisamidateproducts S34.5 may then be separable, e.g. by chromatography.

An example of this procedure is shown in Scheme 34, Example 1. In thisprocedure, a dibenzyl phosphonate S34.14 is reacted withdiazabicyclooctane (DABCO) in toluene at reflux, as described in J. Org.Chem., 1995, 60, 2946, to afford the monobenzyl phosphonate S34.15. Theproduct is then reacted with equimolar amounts of ethyl alaninate S34.16and dicyclohexyl carbodiimide in pyridine, to yield the amidate productS34.17. The benzyl group is then removed, for example by hydrogenolysisover a palladium catalyst, to give the monoacid product S34.18 which maybe unstable according to J. Med. Chem. (1997) 40(23):3842. This compoundS34.18 is then reacted in a Mitsunobu reaction with ethyl leucinateS34.19, triphenyl phosphine and diethylazodicarboxylate, as described inJ. Med. Chem., 1995, 38, 2742, to produce the bisamidate product S34.20.

Using the above procedures, but employing in place of ethyl leucinateS34.19 or ethyl alaninate S34.16, different aminoesters S34.9, thecorresponding products S34.5 are obtained.

Alternatively, the phosphonic acid S34.6 is converted into thebisamidate S34.5 by use of the coupling reactions described above. Thereaction is performed in one step, in which case the nitrogen-relatedsubstituents present in the product S34.5 are the same, or in two steps,in which case the nitrogen-related substituents can be different.

An example of the method is shown in Scheme 34, Example 2. In thisprocedure, a phosphonic acid S34.6 is reacted in pyridine solution withexcess ethyl phenylalaninate S34.21 and dicyclohexylcarbodiimide, forexample as described in J. Chem. Soc., Chem. Comm., 1991, 1063, to givethe bisamidate product S34.22.

Using the above procedures, but employing, in place of ethylphenylalaninate, different aminoesters S34.9, the corresponding productsS34.5 are obtained.

As a further alternative, the phosphonic acid S34.6 is converted intothe mono or bis-activated derivative S34.7, in which Lv is a leavinggroup such as chloro, imidazolyl, triisopropylbenzenesulfonyloxy etc.The conversion of phosphonic acids into chlorides S34.7 (Lv=Cl) iseffected by reaction with thionyl chloride or oxalyl chloride and thelike, as described in Organic Phosphorus Compounds, G. M. Kosolapoff, L.Maeir, eds, Wiley, 1976, p. 17. The conversion of phosphonic acids intomonoimidazolides S34.7 (Lv=imidazolyl) is described in J. Med. Chem.,2002, 45, 1284 and in J. Chem. Soc. Chem. Comm., 1991, 312.Alternatively, the phosphonic acid is activated by reaction withtriisopropylbenzenesulfonyl chloride, as described in Nucleosides andNucleotides, 2000, 10, 1885. The activated product is then reacted withthe aminoester S34.9, in the presence of a base, to give the bisamidateS34.5. The reaction is performed in one step, in which case the nitrogensubstituents present in the product S34.5 are the same, or in two steps,via the intermediate S34.11, in which case the nitrogen substituents canbe different.

Examples of these methods are shown in Scheme 34, Examples 3 and 5. Inthe procedure illustrated in Scheme 34, Example 3, a phosphonic acidS34.6 is reacted with ten molar equivalents of thionyl chloride, asdescribed in Zh. Obschei Khim., 1958, 28, 1063, to give the dichlorocompound S34.23. The product is then reacted at reflux temperature in apolar aprotic solvent such as acetonitrile, and in the presence of abase such as triethylamine, with butyl serinate S34.24 to afford thebisamidate product S34.25.

Using the above procedures, but employing, in place of butyl serinateS34.24, different aminoesters S34.9, the corresponding products S34.5are obtained.

In the procedure illustrated in Scheme 34, Example 5, the phosphonicacid S34.6 is reacted, as described in J. Chem. Soc. Chem. Comm., 1991,312, with carbonyl diimidazole to give the imidazolide S34.32. Theproduct is then reacted in acetonitrile solution at ambient temperature,with one molar equivalent of ethyl alaninate S34.33 to yield themonodisplacement product S34.34. The latter compound is then reactedwith carbonyl diimidazole to produce the activated intermediate S34.35,and the product is then reacted, under the same conditions, with ethylN-methylalaninate S34.33a to give the bisamidate product S34.36.

Using the above procedures, but employing, in place of ethyl alaninateS34.33 or ethyl N-methylalaninate S34.33a, different aminoesters S34.9,the corresponding products S34.5 are obtained.

The intermediate monoamidate S34.3 is also prepared from the monoesterS34.2 by first converting the monoester into the activated derivativeS34.8 in which Lv is a leaving group such as halo, imidazolyl etc, usingthe procedures described above. The product S34.8 is then reacted withan aminoester S34.9 in the presence of a base such as pyridine, to givean intermediate monoamidate product S34.3. The latter compound is thenconverted, by removal of the R¹ group and coupling of the product withthe aminoester S34.9, as described above, into the bisamidate S34.5.

An example of this procedure, in which the phosphonic acid is activatedby conversion to the chloro derivative S34.26, is shown in Scheme 34,Example 4. In this procedure, the phosphonic monobenzyl ester S34.15 isreacted, in dichloromethane, with thionyl chloride, as described in Tet.Letters., 1994, 35, 4097, to afford the phosphoryl chloride S34.26. Theproduct is then reacted in acetonitrile solution at ambient temperaturewith one molar equivalent of ethyl 3-amino-2-methylpropionate S34.27 toyield the monoamidate product S34.28. The latter compound ishydrogenated in ethylacetate over a 5% palladium on carbon catalyst toproduce the monoacid product S34.29. The product is subjected to aMitsunobu coupling procedure, with equimolar amounts of butyl alaninateS34.30, triphenyl phosphine, diethylazodicarboxylate and triethylaminein tetrahydrofuran, to give the bisamidate product S34.31.

Using the above procedures, but employing, in place of ethyl3-amino-2-methylpropionate S34.27 or butyl alaninate S34.30, differentaminoesters S34.9, the corresponding products S34.5 are obtained.

The activated phosphonic acid derivative S34.7 is also converted intothe bisamidate S34.5 via the diamino compound S34.10. The conversion ofactivated phosphonic acid derivatives such as phosphoryl chlorides intothe corresponding amino analogs S34.10, by reaction with ammonia, isdescribed in Organic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir,eds, Wiley, 1976. The bisamino compound S34.10 is then reacted atelevated temperature with a haloester S34.12 (Hal=halogen, i.e. F, Cl,Br, I), in a polar organic solvent such as dimethylformamide, in thepresence of a base such as 4,4-dimethylaminopyridine (DMAP) or potassiumcarbonate, to yield the bisamidate S34.5. Alternatively, S34.6 may betreated with two different amino ester reagents simulataneously, i.e.S34.12 where R^(4b) or R^(5b) are different. The resulting mixture ofbisamidate products S34.5 may then be separable, e.g. by chromatography.

An example of this procedure is shown in Scheme 34, Example 6. In thismethod, a dichlorophosphonate S34.23 is reacted with ammonia to affordthe diamide S34.37. The reaction is performed in aqueous, aqueousalcoholic or alcoholic solution, at reflux temperature. The resultingdiamino compound is then reacted with two molar equivalents of ethyl2-bromo-3-methylbutyrate S34.38, in a polar organic solvent such asN-methylpyrrolidinone at ca. 150° C., in the presence of a base such aspotassium carbonate, and optionally in the presence of a catalyticamount of potassium iodide, to afford the bisamidate product S34.39.

Using the above procedures, but employing, in place of ethyl2-bromo-3-methylbutyrate S34.38, different haloesters S34.12 thecorresponding products S34.5 are obtained.

The procedures shown in Scheme 34 are also applicable to the preparationof bisamidates in which the aminoester moiety incorporates differentfunctional groups. Scheme 34, Example 7 illustrates the preparation ofbisamidates derived from tyrosine. In this procedure, themonoimidazolide S34.32 is reacted with propyl tyrosinate S34.40, asdescribed in Example 5, to yield the monoamidate S34.41. The product isreacted with carbonyl diimidazole to give the imidazolide S34.42, andthis material is reacted with a further molar equivalent of propyltyrosinate to produce the bisamidate product S34.43.

Using the above procedures, but employing, in place of propyl tyrosinateS34.40, different aminoesters S34.9, the corresponding products S34.5are obtained. The aminoesters employed in the two stages of the aboveprocedure can be the same or different, so that bisamidates with thesame or different amino substituents are prepared.

Scheme 35 illustrates methods for the preparation of phosphonatemonoamidates.

In one procedure, a phosphonate monoester S34.1 is converted, asdescribed in Scheme 34, into the activated derivative S34.8. Thiscompound is then reacted, as described above, with an aminoester S34.9,in the presence of a base, to afford the monoamidate product S35.1.

The procedure is illustrated in Scheme 35, Example 1. In this method, amonophenyl phosphonate S35.7 is reacted with, for example, thionylchloride, as described in J. Gen. Chem. USSR., 1983, 32, 367, to givethe chloro product S35.8. The product is then reacted, as described inScheme 34, with ethyl alaninate, to yield the amidate S35.10.

Using the above procedures, but employing, in place of ethyl alaninateS35.9, different aminoesters S34.9, the corresponding products S35.1 areobtained.

Alternatively, the phosphonate monoester S34.1 is coupled, as describedin Scheme 34, with an aminoester S34.9 to produce the amidate S35.1. Ifnecessary, the R¹ substituent is then altered, by initial cleavage toafford the phosphonic acid S35.2. The procedures for this transformationdepend on the nature of the R¹ group, and are described above. Thephosphonic acid is then transformed into the ester amidate productS35.3, by reaction with the hydroxy compound R³OH, in which the group R³is aryl, heterocycle, alkyl, cycloalkyl, haloalkyl etc, using the samecoupling procedures (carbodiimide, Aldrithiol-2, PYBOP, Mitsunobureaction etc) described in Scheme 34 for the coupling of amines andphosphonic acids.

Examples of this method are shown in Scheme 35, Examples and 2 and 3. Inthe sequence shown in Example 2, a monobenzyl phosphonate S35.11 istransformed by reaction with ethyl alaninate, using one of the methodsdescribed above, into the monoamidate S35.12. The benzyl group is thenremoved by catalytic hydrogenation in ethylacetate solution over a 5%palladium on carbon catalyst, to afford the phosphonic acid amidateS35.13. The product is then reacted in dichloromethane solution atambient temperature with equimolar amounts of1-(dimethylaminopropyl)-3-ethylcarbodiimide and trifluoroethanol S35.14,for example as described in Tet. Lett., 2001, 42, 8841, to yield theamidate ester S35.15.

In the sequence shown in Scheme 35, Example 3, the monoamidate S35.13 iscoupled, in tetrahydrofuran solution at ambient temperature, withequimolar amounts of dicyclohexyl carbodiimide and4-hydroxy-N-methylpiperidine S35.16, to produce the amidate esterproduct S35.17.

Using the above procedures, but employing, in place of the ethylalaninate product S35.12 different monoacids S35.2, and in place oftrifluoroethanol S35.14 or 4-hydroxy-N-methylpiperidine S35.16,different hydroxy compounds R³OH, the corresponding products S35.3 areobtained.

Alternatively, the activated phosphonate ester S34.8 is reacted withammonia to yield the amidate S35.4. The product is then reacted, asdescribed in Scheme 34, with a haloester S35.5, in the presence of abase, to produce the amidate product S35.6. If appropriate, the natureof the R¹ group is changed, using the procedures described above, togive the product S35.3. The method is illustrated in Scheme 35, Example4. In this sequence, the monophenyl phosphoryl chloride S35.18 isreacted, as described in Scheme 34, with ammonia, to yield the aminoproduct S35.19. This material is then reacted in N-methylpyrrolidinonesolution at 170° with butyl 2-bromo-3-phenylpropionate S35.20 andpotassium carbonate, to afford the amidate product S35.21.

Using these procedures, but employing, in place of butyl2-bromo-3-phenylpropionate S35.20, different haloesters S35.5, thecorresponding products S35.6 are obtained.

The monoamidate products S35.3 are also prepared from the doublyactivated phosphonate derivatives S34.7. In this procedure, examples ofwhich are described in Synlett., 1998, 1, 73, the intermediate S34.7 isreacted with a limited amount of the aminoester S34.9 to give themono-displacement product S34.11. The latter compound is then reactedwith the hydroxy compound R³OH in a polar organic solvent such asdimethylformamide, in the presence of a base such asdiisopropylethylamine, to yield the monoamidate ester S35.3.

The method is illustrated in Scheme 35, Example 5. In this method, thephosphoryl dichloride S35.22 is reacted in dichloromethane solution withone molar equivalent of ethyl N-methyl tyrosinate S35.23 anddimethylaminopyridine, to generate the monoamidate S35.24. The productis then reacted with phenol S35.25 in dimethylformamide containingpotassium carbonate, to yield the ester amidate product S35.26.

Using these procedures, but employing, in place of ethyl N-methyltyrosinate S35.23 or phenol S35.25, the aminoesters 34.9 and/or thehydroxy compounds R³OH, the corresponding products S35.3 are obtained.

Scheme 36 illustrates methods for the preparation ofcarboalkoxy-substituted phosphonate diesters in which one of the estergroups incorporates a carboalkoxy substituent.

In one procedure, a phosphonate monoester S34.1, prepared as describedabove, is coupled, using one of the methods described above, with ahydroxyester S36.1, in which the groups R^(4b) and R^(5b) are asdescribed in Scheme 34. For example, equimolar amounts of the reactantsare coupled in the presence of a carbodiimide such as dicyclohexylcarbodiimide, as described in Aust. J. Chem., 1963, 609, optionally inthe presence of dimethylaminopyridine, as described in Tet., 1999, 55,12997. The reaction is conducted in an inert solvent at ambienttemperature.

The procedure is illustrated in Scheme 36, Example 1. In this method, amonophenyl phosphonate S36.9 is coupled, in dichloromethane solution inthe presence of dicyclohexyl carbodiimide, with ethyl3-hydroxy-2-methylpropionate S36.10 to yield the phosphonate mixeddiester S36.11.

Using this procedure, but employing, in place of ethyl3-hydroxy-2-methylpropionate S36.10, different hydroxyesters S33.1, thecorresponding products S33.2 are obtained.

The conversion of a phosphonate monoester S34.1 into a mixed diesterS36.2 is also accomplished by means of a Mitsunobu coupling reactionwith the hydroxyester S36.1, as described in Org. Lett., 2001, 643. Inthis method, the reactants 34.1 and S36.1 are combined in a polarsolvent such as tetrahydrofuran, in the presence of a triarylphosphineand a dialkyl azodicarboxylate, to give the mixed diester S36.2. The R¹substituent is varied by cleavage, using the methods describedpreviously, to afford the monoacid product S36.3. The product is thencoupled, for example using methods described above, with the hydroxycompound R³OH, to give the diester product S36.4.

The procedure is illustrated in Scheme 36, Example 2. In this method, amonoallyl phosphonate S36.12 is coupled in tetrahydrofuran solution, inthe presence of triphenylphosphine and diethylazodicarboxylate, withethyl lactate S36.13 to give the mixed diester S36.14. The product isreacted with tris(triphenylphosphine) rhodium chloride (Wilkinsoncatalyst) in acetonitrile, as described previously, to remove the allylgroup and produce the monoacid product S36.15. The latter compound isthen coupled, in pyridine solution at ambient temperature, in thepresence of dicyclohexyl carbodiimide, with one molar equivalent of3-hydroxypyridine S36.16 to yield the mixed diester S36.17.

Using the above procedures, but employing, in place of the ethyl lactateS36.13 or 3-hydroxypyridine, a different hydroxyester S36.1 and/or adifferent hydroxy compound R³OH, the corresponding products S36.4 areobtained.

The mixed diesters S36.2 are also obtained from the monoesters S34.1 viathe intermediacy of the activated monoesters S36.5. In this procedure,the monoester S34.1 is converted into the activated compound S36.5 byreaction with, for example, phosphorus pentachloride, as described in J.Org. Chem., 2001, 66, 329, or with thionyl chloride or oxalyl chloride(Lv=Cl), or with triisopropylbenzenesulfonyl chloride in pyridine, asdescribed in Nucleosides and Nucleotides, 2000, 19, 1885, or withcarbonyl diimidazole, as described in J. Med. Chem., 2002, 45, 1284. Theresultant activated monoester is then reacted with the hydroxyesterS36.1, as described above, to yield the mixed diester S36.2.

The procedure is illustrated in Scheme 36, Example 3. In this sequence,a monophenyl phosphonate S36.9 is reacted, in acetonitrile solution at70° C., with ten equivalents of thionyl chloride, so as to produce thephosphoryl chloride S36.19. The product is then reacted with ethyl4-carbamoyl-2-hydroxybutyrate S36.20 in dichloromethane containingtriethylamine, to give the mixed diester S36.21.

Using the above procedures, but employing, in place of ethyl4-carbamoyl-2-hydroxybutyrate S36.20, different hydroxyesters S36.1, thecorresponding products S36.2 are obtained.

The mixed phosphonate diesters are also obtained by an alternative routefor incorporation of the R³O group into intermediates S36.3 in which thehydroxyester moiety is already incorporated. In this procedure, themonoacid intermediate S36.3 is converted into the activated derivativeS36.6 in which Lv is a leaving group such as chloro, imidazole, and thelike, as previously described. The activated intermediate is thenreacted with the hydroxy compound R³OH, in the presence of a base, toyield the mixed diester product S36.4.

The method is illustrated in Scheme 36, Example 4. In this sequence, thephosphonate monoacid S36.22 is reacted with trichloromethanesulfonylchloride in tetrahydrofuran containing collidine, as described in J.Med. Chem., 1995, 38, 4648, to produce the trichloromethanesulfonyloxyproduct S36.23. This compound is reacted with 3-(morpholinomethyl)phenolS36.24 in dichloromethane containing triethylamine, to yield the mixeddiester product S36.25.

Using the above procedures, but employing, in place of with3-(morpholinomethyl)phenol S36.24, different alcohols R³OH, thecorresponding products S36.4 are obtained.

The phosphonate esters S36.4 are also obtained by means of alkylationreactions performed on the monoesters S34.1. The reaction between themonoacid S34.1 and the haloester S36.7 is performed in a polar solventin the presence of a base such as diisopropylethylamine, as described inAnal Chem., 1987, 59, 1056, or triethylamine, as described in J. Med.Chem., 1995, 38, 1372, or in a non-polar solvent such as benzene, in thepresence of 18-crown-6, as described in Syn. Comm., 1995, 25, 3565.

The method is illustrated in Scheme 36, Example 5. In this procedure,the monoacid S36.26 is reacted with ethyl 2-bromo-3-phenylpropionateS36.27 and diisopropylethylamine in dimethylformamide at 80° C. toafford the mixed diester product S36.28.

Using the above procedure, but employing, in place of ethyl2-bromo-3-phenylpropionate S36.27, different haloesters S36.7, thecorresponding products S36.4 are obtained.

Scheme 37 illustrates methods for the preparation of phosphonatediesters in which both the ester substituents incorporate carboalkoxygroups.

The compounds are prepared directly or indirectly from the phosphonicacids S34.6. In one alternative, the phosphonic acid is coupled with thehydroxyester S37.2, using the conditions described previously in Schemes34-36, such as coupling reactions using dicyclohexyl carbodiimide orsimilar reagents, or under the conditions of the Mitsunobu reaction, toafford the diester product S37.3 in which the ester substituents areidentical.

This method is illustrated in Scheme 37, Example 1. In this procedure,the phosphonic acid S34.6 is reacted with three molar equivalents ofbutyl lactate S37.5 in the presence of Aldrithiol-2 and triphenylphosphine in pyridine at ca. 70° C., to afford the diester S37.6.

Using the above procedure, but employing, in place of butyl lactateS37.5, different hydroxyesters S37.2, the corresponding products S37.3are obtained.

Alternatively, the diesters S37.3 are obtained by alkylation of thephosphonic acid S34.6 with a haloester S37.1. The alkylation reaction isperformed as described in Scheme 36 for the preparation of the estersS36.4.

This method is illustrated in Scheme 37, Example 2. In this procedure,the phosphonic acid S34.6 is reacted with excess ethyl3-bromo-2-methylpropionate S37.7 and diisopropylethylamine indimethylformamide at ca. 80° C., as described in Anal. Chem., 1987, 59,1056, to produce the diester S37.8.

Using the above procedure, but employing, in place of ethyl3-bromo-2-methylpropionate S37.7, different haloesters S37.1, thecorresponding products S37.3 are obtained.

The diesters S37.3 are also obtained by displacement reactions ofactivated derivatives S34.7 of the phosphonic acid with thehydroxyesters S37.2. The displacement reaction is performed in a polarsolvent in the presence of a suitable base, as described in Scheme 36.The displacement reaction is performed in the presence of an excess ofthe hydroxyester, to afford the diester product S37.3 in which the estersubstituents are identical, or sequentially with limited amounts ofdifferent hydroxyesters, to prepare diesters S37.3 in which the estersubstituents are different.

The methods are illustrated in Scheme 37, Examples 3 and 4. As shown inExample 3, the phosphoryl dichloride S35.22 is reacted with three molarequivalents of ethyl 3-hydroxy-2-(hydroxymethyl)propionate S37.9 intetrahydrofuran containing potassium carbonate, to obtain the diesterproduct S37.10.

Using the above procedure, but employing, in place of ethyl3-hydroxy-2-(hydroxymethyl)propionate S37.9, different hydroxyestersS37.2, the corresponding products S37.3 are obtained.

Scheme 37, Example 4 depicts the displacement reaction between equimolaramounts of the phosphoryl dichloride S35.22 and ethyl2-methyl-3-hydroxypropionate S37.11, to yield the monoester productS37.12. The reaction is conducted in acetonitrile at 70° in the presenceof diisopropylethylamine. The product S37.12 is then reacted, under thesame conditions, with one molar equivalent of ethyl lactate S37.13, togive the diester product S37.14.

Using the above procedures, but employing, in place of ethyl2-methyl-3-hydroxypropionate S37.11 and ethyl lactate S37.13, sequentialreactions with different hydroxyesters S37.2, the corresponding productsS37.3 are obtained.

2,2-Dimethyl-2-aminoethylphosphonic acid intermediates can be preparedby the route in Scheme 5. Condensation of 2-methyl-2-propanesulfinamidewith acetone give sulfinyl imine S38.11 (J. Org. Chem. 1999, 64, 12).Addition of dimethyl methylphosphonate lithium to S38.11 afford S38.12.Acidic methanolysis of S38.12 provide amine S38.13. Protection of aminewith Cbz group and removal of methyl groups yield phosphonic acidS38.14, which can be converted to desired S38.15 (Scheme 38a) usingmethods reported earlier on. An alternative synthesis of compound S38.14is also shown in Scheme 38b. Commercially available2-amino-2-methyl-1-propanol is converted to aziridines S38.16 accordingto literature methods (J. Org. Chem. 1992, 57, 5813; Syn. Lett. 1997, 8,893). Aziridine opening with phosphite give S38.17 (Tetrahedron Lett.1980, 21, 1623). Reprotection) of S38.17 affords S38.14.

The invention will now be illustrated by the following non-limitingExamples.

Example 1 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as describedherein.

Specific compounds of the invention can be prepared as follows:

A method of synthesis of compound 1.7 is described in U.S. Pat. No.4,739,073 (column 77, Example 122A in Table II). This material istreated with boron trichloride in dichloromethane to afford the phenol1.8. Phenol 1.8 is then alkylated with a dialkyl ester of aphosphonoalkyltriflate, such as the diiospropyl ester of generalstructure 1.10, which can be prepared as follows:

The product 1.11 is then treated with tertbutyldiphenylsilyl chloride toafford compound 1.12, which is then treated with trimethylsilylbromidein acetonitrile containing collidine to afford the free phosphonate1.13. Compound 1.13 is then converted to the desired prodrug by themethods of phosphonate ester and amidate synthesis outlined below. Thesilyl group is then removed with hydrogen fluoride in pyridine to affordthe compound of general structure 1.14.

Example 2 Preparation of Representative Compounds of the Invention

The synthesis of the hydrolysed beta carboxylic acid forms offluvastatin lactone is illustrated above. Compound 2.1 is hydrolyzed tocompound 2.2 using aqueous sodium hydroxide. The free hydroxyl groupsare protected as the cyclic silyl ether by treatment withditertbutyldichlorosilane in DMF containing imidazole. The carboxylicacid is then protected at the trimethylsilylethyl ester by treatmentwith trimethylsilylethanol and dicyclohexylcarbodiimide in DMF to affordcompound 2.3. Compound 2.3 is then treated with trimethylsilyl bromidein acetonitrile containing collidine to afford the compound of thegeneral structure 2.4. The phosphonic acid 2.4 is then converted to thedesired prodrug form by the methods of phosphonic acid ester and amidateformation outlined below, and the protecting groups are removed withhydrogen fluoride in pyridine to afford the prodrug of the generalstructure 2.6.

Specific compounds of the invention are prepared as follows:

The synthesis of 2.12, which is a member of the class of compounds moregenerally described by 1.14, is described. Compound 2.7 is preparedaccording to Example 1, and the free phenolic hydroxyl group is thenselectively alkylated with diisopropyltrifluoromethylsulfonyloxymethylphosphonate in a solvent such as DMFusing cesium carbonate, magnesium tert-butoxide or any other suitablebase to yield the phosphonyl ether 2.8. The free hydroxyl group of 2.8is then protected by treatment with tertbutyldiphenylsilyl chloride inDMF containing imidazole to yield the protected phosphonate diester 2.9.The alkyl protecting groups of the phosphonate moiety are then removedwith trimethylsilylbromide in acetonitrile containing a base such ascollidine to yield 2.10. The free phosphonate 2.10 is converted into themonophenol derivative with dicyclohexylcarbodiimide in DMF, and thencondensed with the isopropyl ester of alanine, under the action oftriphenyl phosphine and aldrithiol to yield compound 2.11. The silylprotecting group of 2.11 is removed with buffered fluoride source suchas hydrogen fluoride in pyridine, yielding the prodrug of the lactone ofstructure 2.12.

An additional specific compound of the invention may be prepared asfollows:

The synthesis of 2.18, a member of the class of compounds more generallydescribed by structure 2.6 is shown above. Compound 2.8, prepared asdescribed above, is hydrolyzed to compound 2.13 using aqueous sodiumhydroxide. The free hydroxyl groups are protected as the cyclic silylether by treatment with ditertbutyldichlorosilane in DMF containingimidazole. The carboxylic acid is then protected at thetrimethylsilylethyl ester by treatment with trimethylsilylethanol anddicyclohexylcarbodiimide in DMF to afford compound 2.14. Compound 2.14is then treated with trimethylsilyl bromide in acetonitrile containingcollidine to afford the compound of the general structure 2.15. The freephosphonate 2.15 is converted into the monophenol derivative 2.16 withdicyclohexylcarbodiimide in DMF, and then condensed with the isopropylester of alanine, under the action of triphenyl phosphine and aldrithiolto yield compound 2.17. The silyl protecting group of 2.17 is removedwith buffered fluoride source such as hydrogen fluoride in pyridine,yielding the prodrug 2.18.

Example 3 Preparation of Representative Compounds of the Invention

In general, representative compounds of the invention can be made asfollows:

Specific compounds of the invention can be prepared as follows:

A generic phosphonate bis-ester can be prepared as demonstrated aboveand the substituents at phosphorus can be manipulated according totransformations shown herein. The synthesis begins with formation ofsilyl enol ether of methyl acetoacetate (available from Aldrich) usingTMSCl and LDA as described in Jullien et al., Tetrahedron Lett.,23(47):4943 (1982) to form compound 3.1. Bromination under theconditions reported by Chan et al., J. Chem. Soc. Chem. Commun., 578(1979) yields 4-bromo-3-oxo-butyric acid methyl ester 3.2. Arbuzovreaction of the bromide 3.2 with triethylphosphite as reported by Yuanet al:, Heteroatom Chemistry, 13(2):153 (2002) provides diethylphosphonate 3.3. Addition of ester 3.3 to bakers' yeast in water yields4-(diethoxyphosphoryl)-3-R-hydroxybutanoic acid methyl ester 3.4 asdescribed by Yuan, E. et al. Silylation of the newly generated secondaryalcohol using TBSCl and imidazole followed by selective removal of themethyl ester protecting group as described in Greene, T., “ProtectiveGroups in Organic Synthesis, Wiley-Interscience (1999) provides compound3.5. Carboxylic acid 3.5 is treated with methyl chloroformate andtriethylamine to give a mixed anhydride which is then converted tocompound 3.6 by reacting with methylidenetriphenylphosphorane accordingto the method described in Konoike et al., J. Org. Chem., 59:7849(1994). A Wittig reaction between compound 3.6 and aldehyde 3.6.1(prepared as described in WO 84/12131) provides the olefin analog 3.7.Removal of the TBS protecting group with HF in MeCN followed bystereoselective chelation-controlled reduction with Et₂BOMe and sodiumborohydride in THF: MeOH gives the desired phosphonate 3.8.

An example of the synthesis of a representative compound of theinvention is depicted above. A Sonagashira coupling (see Stang, P. J.and Diederich, F., Metal Catalyzed Cross Coupling Reactions, Wiley-VCH,Weinheim, (1988)) is used to attach the phosphonate moiety. Therequisite acetylene is made by heating 5-chloro-1-pentyne withtriethylphosphite in a solvent such as toluene (or other Arbuzovreaction conditions: see Engel, R., “Synthesis of Carbon-phosphorusBonds,” CRC press, (1988)), and the aryl bromide by the analogous routeas for fluvastatin itself.

Example 4 Preparation of Representative Compounds of the Invention

Compounds such as Pitavastatin, 4.1, and its opened chain form, 4.2, areuseful for inhibiting chloesterol biosynthesis and lowering bloodcholesterol levels. As such, they are useful in the treatment ofatherosclerosis hypercholesterolemia and hyper lipoproteinemia asdescribed in U.S. Pat. No. 5,856,336 (Column 1, line 40).

The present invention provides novel analogs of Pitavastatin, 4.1, andits opened chain form, 4.2. Such novel analogs, e.g., general structures4.3 and 4.4, above, possess all the utilities of Pitavastatin and itsopened chain form, and optionally provide cellular accumulation.

Representative compounds of the invention can be prepared as describedherein.

Specific compounds of the invention can be prepared as follows:

A method of synthesis of compound 4.7 is described in U.S. Pat. No.5,856,336 (column 11, in Table 1). This material is treated with borontrichloride in dichloromethane to afford the phenol 4.8. Phenol 4.8 isthen alkylated with a dialkyl ester of a phosphonoalkyltriflate, such asthe diiospropyl ester of general structure 4.10, which can be preparedas follows:

The product 4.11 is then treated with tertbutyldiphenylsilyl chloride toafford compound 4.12, which is then treated with trimethylsilylbromidein acetonitrile containing collidine to afford the free phosphonate4.13.

Compound 4.13 is then converted to the desired prodrug by the methods ofphosphonate ester and amidate synthesis outlined below. Then, the silylgroup is removed with hydrogen fluoride in pyridine to afford thecompound of general structure 4.14.

Example 5 Preparation of Representative Compounds of the Invention

The synthesis of the hydrolysed beta carboxylic acid forms offluvastatin lactone is shown above.

Compound 5.1 is hydrolyzed to compound 5.2 using aqueous sodiumhydroxide. The free hydroxyl groups are protected as the cyclic silylether by treatment with ditertbutyldichlorosilane in DMF containingimidazole. The carboxylic acid is then protected at thetrimethylsilylethyl ester by treatment with trimethylsilylethanol anddicyclohexylcarbodiimide in DMF to afford compound 5.3. Compound 5.3 isthen treated with trimethylsilyl bromide in acetonitrile containingcollidine to afford the compound of the general structure 5.4.

The phosphonic acid 5.4 is then converted to the desired prodrug form bythe methods of phosphonic acid ester and amidate formation outlinedbelow, and the protecting groups are removed with hydrogen fluoride inpyridine to afford the prodrug of the general structure 5.6.

Specific compounds of the invention can be prepared as follows:

The synthesis of compound 5.13 is illustrated above. Compound 5.8 isprepared according to Example 4, and the free phenolic hydroxyl group isthen selectively alkylated with diisopropyltrifluoromethylsulfonyloxymethylphosphonate in a solvent such as DMFusing cesium carbonate, magnesium tert-butoxide or any other suitablebase to yield the phosphonyl ether 5.9. The free hydroxyl group of 5.9is then protected by treatment with tertbutyldiphenylsilyl chloride inDMF containing imidazole to yield the protected phosphonate diester5.10. The alkyl protecting groups of the phosphonate moiety are thenremoved with trimethylsilylbromide in acetonitrile containing a basesuch as collidine to yield 5.11. The free phosphonate 5.11 is convertedinto the monophenol derivative with dicyclohexylcarbodiimide in DMF, andthen condensed with the isopropyl ester of alanine, under the action oftriphenyl phosphine and aldrithiol to yield compound 5.12. The silylprotecting group of 5.12 is removed with buffered fluoride source suchas hydrogen fluoride in pyridine, yielding the prodrug of the lactone ofstructure 5.13.

Example 6 Preparation of Representative Compounds of the Invention

Specific compounds of the invention can be prepared as follows:

The synthesis of 6.7, a member of the class of compounds more generallydescribed in Example 4 (compound 4.6), is depicted above. Compound 6.1is prepared as described herein. Compound 6.1 is hydrolyzed to compound6.2 using aqueous sodium hydroxide and the free hydroxyl groups areprotected as the cyclic silyl ether by treatment withditertbutyldichlorosilane in DMF containing imidazole. The carboxylicacid is then protected at the trimethylsilylethyl ester by treatmentwith trimethylsilylethanol and dicyclohexylcarbodiimide in DMF to affordcompound 6.3. Compound 6.3 is then treated with trimethylsilyl bromidein acetonitrile containing collidine to afford the compound of thegeneral structure 6.4. The free phosphonate 6.4 is converted into themonophenol derivative 6.5 with dicyclohexylcarbodiimide in DMF, and thencondensed with the isopropyl ester of alanine, under the action oftriphenyl phosphine and aldrithiol to yield compound 6.6. The silylprotecting group of 6.6 is removed with buffered fluoride source such ashydrogen fluoride in pyridine, yielding the prodrug 6.7.

Example 7 Preparation of Representative Compounds of the Invention

Representative compounds can be made according to the following:

The preparation of analog 7.8, e.g., 7.17, is shown above. A genericphosphonate bis-ester can be prepared as demonstrated above and thesubstituents at phosphorus can be manipulated according totransformations.

A specific compound of the invention, 7.17, is also shown above. Thesynthesis begins with formation of silyl enol ether ofmethylacetoacetate (available from Aldrich) using TMSCl and LDA asdescribed in Jullien et al., Tetrahedron Lett., 23(47):4943 (1982) toform compound 7.1. Bromination under the conditions reported by Chan etal., J. Chem. Soc. Chem. Commun., 578 (1979) yields4-bromo-3-oxo-butyric acid methyl ester 7.2. Arbuzov reaction of thebromide 7.2 with triethylphosphite as reported by Yuan et al.,Heteroatom Chemistry, 13(2):153 (2002) provides diethyl phosphonate 7.3,e.g., 7.9. Addition of ester 7.3 to bakers' yeast in water yields4-(diethoxyphosphoryl)-3-R-hydroxybutanoic acid methyl ester 7.4 asdescribed by Yuan et al. Silylation of the newly generated secondaryalcohol using TBSCl and imidazole followed by selective removal of themethyl ester protecting group as described in Greene, T., “ProtectiveGroups in Organic Synthesis,” Wiley-Interscience (1999) providescompound 7.5. Carboxylic acid 7.5 is treated with methyl chlorocarbonateand triethylamine to give a mixed anhydride which is then converted tocompound 7.6 by reacting with methylidenetriphenylphosphorane accordingto the method described in Konoike et al., J. Org. Chem., 59:7849(1994). A Wittig reaction between compound 7.6 and aldehyde 7.6.1(prepared according to D. R. Sliskovic et al., J. Med. Chem., 34:367(1991)) provides the olefin analog 7.7. Removal of the TBS protectinggroup with HF in MeCN followed by stereoselective chelation-controlledreduction with Et₂BOMe and sodium borohydride in THF: MeOH gives thedesired phosphonate 7.8.

An example of the synthesis of a compound of the invention is depictedbelow.

A Sonagashira coupling (see Stang, P. J. and Diederich, F., “MetalCatalyzed Cross Coupling Reactions,” Wiley-VCH, Weinheim (1988)) is usedto attach the phosphonate moiety. The requisite acetylene is made byheating 5-chloro-1-pentyne with triethylphosphite in a solvent such astoluene (or other Arbuzov reaction conditions: see Engel, R., “Synthesisof Carbon-phosphorus Bonds,” CRC press (1988)), and the aryl bromide bythe same route as described for other pitavastatin analogs (Sliskovic etal., J. Med. Chem., 34:367 (1991)), starting from2-bromo-4-fluoro-2′-aminobenzophenone.

Example 8 Preparation of Representative Compounds of the Invention

The synthesis of representative compounds of the invention is describedbelow.

The preparation of intermediate 8.9 is described in U.S. Pat. No.4,444,784 and the references within.

The side chain containing the phosphonate moiety, carboxylic acid 8.8,can be prepared from alpha methyl gamma butyrolactone. First, theracemic lactone is resolved using a chiral preparative HPLC column, andthe S isomer is hydrolized with lithium hydroxide in aqueoustetrahydrofuran. The resulting acid is converted to its tert butyl esterwith isobutene and sulfuric acid. Then, the ester is alkylated withdiisopropylphosphonomethylbromide in dimethylformamide using sodiumhydride as the base to afford compound 8.7. Compound 8.7 is thendeprotected with trifluoroaceic acid to afford the synthon 8.8.

The coupling between intermediate 8.9 and carboxylic acid 8.8 iseffected through the action of dicyclohexylcarbodiimide in DMF to affordthe phosphonate containing protected lovastatin analog 8.10. Theisopropyl groups are removed with trimethylsilylbromide in acetonitrilecontaining collidine to afford the free phosphonic acid 8.11.Phosphonate 8.11 can then be converted into a variety of phosphonicester as described by the general structure 8.15 by the methods ofphosphonate interconversion described below. In this example, 8.11 istreated with dicyclohexycarbodiimide and phenol to afford the monoester8.12, which is further condensed with alanine isopropyl ester usingaldrithiol and triphenylphosphine to afford 8.13. Finally, intermediate8.13 is deprotected with hydrogen fluoride in pyridine to afford thedesired compound 8.14

Example 9 Preparation of Representative Compounds of the Invention

Representative compounds of the invention, e.g., as shown above, can bemade according to the following:

Preparation of analog 9.8, e.g., 9.14, is shown above. A genericphosphonate bis-ester can be prepared as demonstrated above and thesubstituents at phosphorus can be manipulated according totransformations. A specific example for compound 9.8 is shown.

The synthesis begins with formation of silyl enol ether ofmethylacetoacetate (available from Aldrich) using TMSCl and LDA asdescribed in Jullien et al., Tetrahedron Lett., 23(47):4943 (1982) toform compound 9.1. Bromination under the conditions reported by Chan etal., J. Chem. Soc. Chem. Commun., 578 (1979) yields4-bromo-3-oxo-butyric acid methyl ester 9.2. Arbuzov reaction of thebromide 9.2 with triethylphosphite as reported by Yuan et al.,Heteroatom Chemistry, 13(2):153 (2002) provides diethyl phosphonate 9.9.Addition of ester 9.9 to bakers' yeast in water yields4-(diethoxyphosphoryl)-3-R-hydroxybutanoic acid methyl ester 9.10 asdescribed by Yuan, E. et al. Silylation of the newly generated secondaryalcohol using TBSCl and imidazole followed by selective removal of themethyl ester protecting group as described in Greene, T., “ProtectiveGroups in Organic Synthesis,” Wiley-Interscience (1999) providescompound 9.11. Carboxylic acid 9.11 is treated with methylchlorocarbonate and triethylamine to give a mixed anhydride which isthen converted to compound 9.12 by reacting withmethylidenetriphenylphosphorane according to the method described inKonoike et al., J. Org. Chem., 59:7849 (1994). A Wittig reaction betweencompound 9.6 and aldehyde 9.6.1 (prepared according to U.S. Pat. No.5,006,530) provides the olefin analog 9.13. Removal of the TBSprotecting group with HF in MeCN followed by stereoselectivechelation-controlled reduction with Et₂BOMe and sodium borohydride inTHF: MeOH gives the desired phosphonate 9.11.

An example of the synthesis of an analog of a compound of the inventionis depicted above. A Sonagashira coupling (see Stang, P. J. andDiederich, F., “Metal Catalyzed Cross Coupling Reactions,” Wiley-VCH,Weinheim, (1988)) is used to attach the phosphonate moiety. Therequisite acetylene is made by heating 5-chloro-1-pentyne withtriethylphosphite in a solvent such as toluene (or other Arbuzovreaction conditions see Engel, R., “Synthesis of Carbon-phosphorusBonds, CRC press, (1988)), and the aryl bromide by the analogous routeas for cerivastatin itself (U.S. Pat. No. 5,006,530).

Example 10 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as follows:

The linkage between the phosphonate moiety and Cerivastatin can beformed by alkylating the free hydroxyl group of intermediate 10.1, whosesynthesis is described in U.S. Pat. No. 5,006,530, (column 65, line 5).

Compound 10.1 is reacted with ditetbutyldichlorosilane in pyridine toafford the protected intermediate 10.2. The free hydroxyl group ofcompound 10.2 is alkylated with an alkyl protected phosphonoalkylhalidesuch as diisopropylphoshonomethylbromide to afford the conjugate 10.3.The methyl ester of compound 10.3 is exchanged for thetrimethylsilylethylester by hydrolysis with lithium hydroxide, followedby coupling with trimethylsilylethanol with dicyclohexycarbodiimide inDMF, followed by the removal of the phosphonate protecting groups withtrimethylsilylbromide and collidine in acetonitrile to yield compound10.4.

Compound 10.4 is then transformed into the desired prodrug form by themethods of phosphonic acid transformation described below, and the silylprotecting groups are removed with a fluoride source such as hydrogenfluoride in pyridine to yield the desired prodrug of the generalstructure 10.6.

Specific compounds of the invention, conforming to the descriptionrendered by the general structure 10.6, can be synthesized as follows:

Compound 10.7 is alkylated with the commercially available diisopropylphosphonomethylbromide in DMF with cesium carbonate as base. Theresulting phosphonate 10.8 is treated with lithium hydroxide. Theresulting carboxylic acid is coupled to trimethylsilylethanol to yieldthe trimethylsilylethylester. Removal of the isopropyl esters withtrimethylsilylbromide in collidine and DMF affords the phosphonic acid10.9, which is then coupled with phenol with dicyclohexylcarbodiimide inDMF to afford compound 10.10. Compound 10.10 is then coupled with theisopropyl ester of alanine using triphenylphosphine and aldrithiol inDMF to afford compound 10.11. The silyl protecting groups of 10.11 arethen removed with a hydrogen fluoride in pyridine to afford the desiredprodrug 10.12.

Example 11 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be synthesized as follows:

The preparation of compound 11.1, also known as M-4 lactone, isdescribed in U.S. Pat. No. 4,346,227. (See column 10, line 30.) Compound11.1, is treated with one equivalent of a silyl based protecting group,such as tert-butyldimethylsilyl in a solvent such as DMF with imidazoleserving as base, to yield a mixture of unsilylated, mono-silylated andbis-silylated derivatives 11.1, 11.2, 11.3, and 11.4.

The desired compound 11.4 is separated by chromatography, such as silicagel chromatography or reverse phase chromatography. The free hydroxylgroup is then alkylated with a dialkyl protectedtrifluoromethylsulfonylalkylphosphonate of general structure 11.6 (thesynthesis of which is described below) in a solvent such as DMF usingcesium carbonate, magnesium tert-butoxide or any other suitable base toyield the phosphonyl ether of general structure 11.7. The alkylprotecting groups of the phosphonate moiety are then removed withtrimethylsilylbromide in acetonitrile containing a base such ascollidine. The free phosphonate is then converted into the desiredprodrug of general structure 11.9 by the methods of phosphonic acidinterconversions described herein. The silyl protecting group of 11.9 isremoved with buffered fluoride source such as hydrogen fluoride inpyridine, yielding the prodrug of the lactone of general structure11.10.

Upon oral administration of this prodrug, normal mammalian metabolicprocesses are able to hydrolyse lactones such as 11.10 to thecorresponding dihydroxycarboxylic acid, as exemplified by Example 19 ofU.S. Pat. No. 4,346,227 (column 15, line 55).

Synthesis of 11.6 is described as follows:

The synthesis specific compounds of the invention, in particular,prodrugs 11.17 and 11.18, is described as follows:

Compound 11.4 is prepared as discussed above. The free hydroxyl group isthen alkylated with diisopropyltrifluoromethylsulfonyloxymethylphosphonate 11.12, in a solvent such asDMF using cesium carbonate, magnesium tert-butoxide or any othersuitable base to yield the phosphonyl ether 11.13. The alkyl protectinggroups of the phosphonate moiety are then removed withtrimethylsilylbromide in acetonitrile containing a base such ascollidine to yield 11.14 and the free phosphonate is converted into themonophenol derivative 11.15 with dicyclohexylcarbodiimide in DMF.Compound 11.15 is then condensed with the isopropyl ester of alanineunder the action of triphenyl phosphine and aldrithiol to yield 11.16.The silyl protecting group of 11.16 is removed with buffered fluoridesource such as hydrogen fluoride in pyridine, yielding the prodrug ofthe lactone of structure 11.17. Upon oral administration of thisprodrug, normal mammalian metabolic processes are able to convert it tothe corresponding dihydroxycarboxylic acid of structure 11.18.

Example 12 Preparation of Representative Compounds of the Invention

Representative compounds can be made according to the general routeoutlined below.

The preparation of analog 12.8 is described above. A phosphonatebis-ester can be prepared as shown. The substituents at phosphorus canbe manipulated according to transformations described herein.

An example of the synthesis of specific compounds of the invention isshown below.

The synthesis begins with the formation of silyl enol ether of methylacetoacetate (available from Aldrich) using TMSCl and LDA as describedin Jullien et al., Tetrahedron Lett. 23:47, 4943 (1982) to form compound12.1. Bromination under the conditions reported by Chan et al., J. Chem.Soc. Chem. Commun., 578 (1979) yields 4-bromo-3-oxo-butyric acid methylester 12.2. Arbuzov reaction of the bromide 12.2 with triethyl phosphiteas reported by Yuan et al., Heteroatom Chemistry, 13:2, 153 (2002)provides diethyl phosphonate 12.9. Addition of ester 12.9 to bakers'yeast in water yields 4-(diethoxyphosphoryl)-3-R-hydroxybutanoic acidmethyl ester 12.10 as described by Yuan et al.

Silylation of the newly generated secondary alcohol using TBSCl andimidazole followed by selective removal of the methyl ester protectinggroup as described in Greene, T., “Protective Groups in OrganicSynthesis,” Wiley-Interscience (1999) provides compound 12.11.Carboxylic acid 12.11 is treated with methyl chloroformate andtriethylamine to give a mixed anhydride that is then converted tocompound 12.12 by reacting with methylidenetriphenylphosphoraneaccording to the method described in Konoike et al., J. Org. Chem.,59:7849 (1994).

A Wittig reaction between compound 12.12 and aldehyde 12.13 (preparedaccording to Watanabe et al., Bioorg. & Med. Chem., 5:437 (1997))provides the olefin analog 12.14. Removal of the TBS protecting groupwith HF in MeCN followed by stereoselective chelation-controlledreduction with Et₂BOMe and sodium borohydride in THF: MeOH gives thedesired phosphonate 12.15.

A representative compound of the invention may be synthesized asillustrated below:

Preparation of the desired aldehyde 12.20 is shown. The startingmaterial 12.16 is prepared as reported in Danishefsky. et al., J. Am.Chem. Soc., 111:2599 (1989). The silylenolether 12.16 can be reactedwith m-chloroperbenzoic acid in hexanes, followed by acidic workup andesterification with diazomethane to provide compound 12.17. Protectionof the secondary alcohol as the acetate followed by reduction of theketone and generation of the mesylate allows for elimination to providediene 12.18. Reduction of the methylester using DIBAH followed by Swernoxidation of the primary alcohol to aldehyde creates compound 12.19.Installation of a variety of esters are possible after removal of theTBS group according to the procedure of Hoffman, et al., J. Med. Chem.29:849 (1986). After protecting group manipulations, the isobutyrylgroup is installed using isobutyryl chloride in pyridine containing DMAPto provide compound 12.20.

Representative compounds of the invention can be made according to thegeneral route outlined below:

Formation of pro-drug 12.21, e.g., 12.22, is shown. Formation of anappropriate acylating reagent, (1-chlorocarbonyl-propyl)-phosphonic aciddiethyl ester, can be achieved from the benzyl protected carboxylic acid(Salvino et al., J. Org. Chem., 64(6):1823 1999)) after removal of thebenzyl group and formation of the acid chloride using standardreactions. Acylation of the hindered axial alcohol can be achieved afterprotection of the other free secondary alcohol in the substrate, usingthis reagent in pyridine containing DMAP according to the procedure ofHoffman et al., J. Med. Chem., 29:849 (1986). Removal of the TBSprotecting groups is achieved using TBAF to provide pro-drug 12.21, suchas 12.22.

Example 13 Preparation of Representative Compounds of the Invention

A synthetic scheme for the preparation of compounds of the invention isas follows:

The de-acylation and re-acylation of pravastatin is disclosed in EP0609058 A2.

In addition, representative compounds of the invention may be preparedas follows:

The oxime formation is disclosed in Bioorg. Med. Chem., 3:1479 (1995).

Example 14 Preparation of Representative Components of the Invention

The preparation of representative compounds of the invention isdescribed as follows:

Intermediate 14.1 is described in U.S. Pat. No. 4,444,784 and referenceswithin. Intermediates for the synthesis of compounds containing theether linkage between the phosphonate and Simvastatin moiety can beconstructed as follows:

Intermediate 14.1 is treated with an protected alkylphosphonate bearinga leaving group and a base to afford the phosphonomethyl Simvastatinconjugate 14.2. 14.2 is then dealkylated with trimethylsilyl bromide toafford the protected phosphonic acid 14.3, which is then converted tothe desired prodrug using the methods of interconversion of phosphonatesand their prodrugs as described herein, and removal of the silylprotecting group with a fluoride source.

An example of the synthesis of specific compounds of the invention isillustrated below:

The intermediate 14.1 is treated with diisopropylphosphonomethyltriflate in pyridine to afford the conjugate 14.4. Although in thisexample triflate is the leaving group and the phosphonate is protectedas the diisopropyl ester, any other suitable leaving groups can be used,such as tosyl, mesyl, benzenesulfonyl, bromo, iodo, chloro, and soforth. The phosphonate moiety can be protected with any suitable groupincluding, but not limited to, methyl, ethyl, phenyl, substituted phenylbenzyl, substituted benzyl, cyanoethyl, nitrophenethyl and so forth, aslong as the conditions for deprotection are compatible with thestability of the conjugate and the deprotected conjugate. Furthermore,the conjugate 14.4 is deprotected. In this example, it is deprotectedwith trimethylsilyl bromide in a suitable solvent such as acetonitrile,dichloromethane, dimethylformamide, or any other solvent compatible withthe reactivity of the deprotection agent containing a base such aspyridine, collidine, or lutidine, or any other suitable organic orinorganic base to afford the phosphonate 14.5.

Phosphonate 14.5 can then be converted to the desired prodrug by themethods described herein. In this example, 14.5 is treated withdicyclohexycarbodiimide and phenol to afford the monoester 14.6, whichis further condensed with alanine isopropyl ester using aldrithiol andtriphenylphosphine to afford 14.7. Finally, intermediate 14.7 isdeprotected with hydrogen fluoride in pyridine to afford the desiredcompound 14.8.

The synthesis of compounds of the invention containing an ester is shownbelow:

Intermediate 14.1 is treated with a protected alkylphosphonocarboxylicacid bearing a leaving group such as halogen, pentafluorophenol, or anyother such group normally used to activate a carboxylic acid forcoupling to an alcohol and a base to afford the phosphonomethylSimvastatin conjugate 14.9. Compound 14.9 is then dealkylated withtrimethylsilyl bromide to afford the protected phosphonic acid 14.10,which is then converted to the desired prodrug using the methods ofinterconversion of phosphonates and their prodrugs as described herein,and removal of the silyl protecting group with a fluoride source.

Specific compounds of the invention can also be prepared as follows:

The intermediate 14.1 is treated with the protected phosphonoacetylchloride, prepared form the commercially availablediethylphosphonoacetic acid by the action of thionyl chloride, inpyridine to afford the conjugate 14.11. The conjugate 14.11 isdeprotected, in this example with trimethylsilyl bromide in a suitablesolvent such as acetonitrile, dichloromethane, dimethylformamide, or anyother solvent compatible with the reactivity of the deprotection agentcontaining a base such as pyridine, collidine, lutidine or any othersuitable organic or inorganic base to afford the phosphonate 14.12.

Phosphonate 14.12 can then be converted to the desired prodrug by thefollowing methods. 14.12 is treated with dicyclohexycarbodiimide andphenol to afford the monoester 14.13, which is further condensed withalanine isopropyl ester using aldrithiol and triphenylphosphine toafford intermediate 14.14. Finally, intermediate 14.14 is deprotectedwith hydrogen fluoride in pyridine to afford the desired compound 14.15.

A representative compound of the invention containing a carbamatelinkage can be prepared as follows:

Intermediate 14.6 is treated with phosgene or a carbonate derivativebearing two active leaving groups to afford the activated intermediate14.16. This intermediate is treated with a protected phosphonoalkylamine and a base to afford the phosphonoalkylcarbamoyl ester ofSimvastatin 14.17. 14.17 is then dealkylated with trimethylsilyl bromideto afford the protected phosphonic acid 14.18. 14.18 is then convertedto the desired prodrug using the methods of interconversion ofphosphonates and their prodrugs as described herein, and removal of thesilyl protecting group with a fluoride source.

Another example of the synthesis of specific compounds of the inventionis presented below:

The intermediate 14.6 is treated with phosgene in dichloromethanecontaining diisoproylethylamine to afford the chloroformate 14.19. Theintermediate 14.19 is reacted with the commercially availablediethylphosphonomethylamine yielding the protected conjugate 14.20. Thephosphonate moiety is then deprotected, in this example, withtrimethylsilyl bromide in a suitable solvent such as acetonitrile,dichloromethane, dimethylformamide, or any other solvent compatible withthe reactivity of the deprotection agent containing a base such aspyridine, collidine, or lutidine or any other suitable organic orinorganic base to afford the phosphonic acid 14.21.

Phosphonic acid 14.21 can then be converted to the desired prodrug bythe methods described herein. In this example, 14.21 is treated withdicyclohexycarbodiimide and phenol to afford the monoester 14.22, whichis further condensed with alanine isopropyl ester using aldrithiol andtriphenylphosphine to afford intermediate 14.23. Finally, intermediate14.23 is deprotected with hydrogen fluoride in pyridine to afford thedesired compound 14.24.

Example 15 Preparation of Representative Compounds of the Invention

Representative compounds of the invention such as those illustratedabove can be made according to the following:

The preparation of analog 15.8 is shown above. A phosphonate bis-estercan be prepared as demonstrated above and the substituents at phosphoruscan be manipulated according to transformations. The synthesis of aspecific example for compound 15.8, i.e., 15.14, is also shown.

The synthesis begins with formation of silyl enol ether of methylacetoacetate (available from Aldrich) using TMSCl and LDA as describedin Jullien et al., Tetrahedron Lett., 23(47):4943 (1982) to formcompound 15.1. Bromination under the conditions reported by Chan et al.,J. Chem. Soc. Chem. Commun., 578 (1979) yields 4-bromo-3-oxo-butyricacid methyl ester 15.2. Arbuzov reaction of the bromide 15.2 withtriethylphosphite as reported by Yuan et al., Heteroatom Chemistry,13(2): 153 (2002) provides diethyl phosphonate 15.3. Addition of ester15.3 to bakers' yeast in water yields4-(diethoxyphosphoryl)-3-R-hydroxybutanoic acid methyl ester 15.4 asdescribed by Yuan et al. Silylation of the newly-generated secondaryalcohol using TBSCl and imidazole followed by selective removal of themethyl ester protecting group as described in Greene, T., “ProtectiveGroups in Organic Synthesis,” Wiley-Interscience (1999) providescompound 15.5. Carboxylic acid 15.5 is treated with methyl chloroformateand triethylamine to give a mixed anhydride which is then converted tocompound 15.6 by reacting with methylidenetriphenylphosphorane accordingto the method described in Konoike et al., J. Org. Chem., 59:7849(1994). A Wittig reaction between compound 15.6 and aldehyde 15.6.1(prepared according to WO 9,302,089 and U.S. Pat. No. 4,950,775)provides the olefin analog 15.7. Removal of the TBS protecting groupwith HF in MeCN followed by stereoselective chelation-controlledreduction with Et₂BOMe and sodium borohydride in THF: MeOH gives thedesired phosphonate 15.8.

Representative compounds such as 15.17 can be made according to thefollowing:

Installation of the prodrug moiety on the methyl substitution of thedecalin system to provide pro-drug 15.17 is shown above. Startingmaterial 15.15, described in WO 93/02089, undergoes dihydroxylationfollowed by cleavage of the diol to provide aldehyde 15.16. A one-stepreductive amination reaction using mild reducing agents such as sodiumcyanoborohydride or sodium triacetoxyborohydride in alcoholic solutionyields the desired pro-drug 15.17, e.g., 15.18.

Example 16 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be synthesized asdescribed herein.

The linkage between the phosphonate moiety and Atorvastatin can beformed by substituting the phenyl ring at R⁴⁴ or the phenyl ring at R³³with an amino group as described herein below and then conjugating theamino group with a protected phosphonoalkylaldehyde of the generalstructure 16.23, by reductive alkylation. The substitution can be ortho,meta or para to the point of attachment of the phenyl ring.

For compounds of the invention substituted at the R⁴⁴ position, a methodof synthesis is as follows:

The synthesis of intermediate 16.4 is described in U.S. Pat. No.4,681,893 (column 4, line 50). Compound 16.4 is reacted according to theprocedure disclosed in U.S. Pat. No. 4,681,893 with anacetylenecarboxamide of the general structure 16.3, derived from ortho,para or meta nitro-aniline 16.1 by protection of the amino group as thet-butylcarbamate to yield, followed by the reduction of the nitro groupby hydrogenation with hydrogen and a catalyst such as palladium oncarbon in a suitable solvent such as ethanol, methanol or ethyl acetate,compound 16.2.

The acylation of the newly formed amino group with the acyl chloride ofphenylpropynoic acid yields the pyrrole 16.4, after mild aqueoushydrolysis of the acetal moiety. The derivative 16.4 is then condensedwith the dianion of ethyl acetylacetate followed by reduction of thecarbonyl moiety and hydrolysis of the acid ester to yield the pyrrole ofgeneral structure 16.5. The resulting beta hydroxy carboxylic acid 16.5is then treated with an acid such as trifluoroacetic acid in anappropriate anhydrous aprotic solvent to deprotect the masked anilinefunction to yield compound 16.6. A compound of general structure 16.6 isthen treated with an aldehyde of general structure 16.23 (the synthesisof which is described below), and the reductive alkylation is effectedwith the addition of a reducing agent such as sodium cyanoborohydride,or by catalytic hydrogenation with a catalyst such as palladium oncharcoal in a solvent such as ethanol, methanol, ethyl acetate, or DMFto afford the desired compound.

Specific compounds of the invention can be prepared as follows:

The commercially available tert-butoxycarbonyl protectedp-phenylenediamine 16.8 is treated with the acid chloride prepared fromphenylpropynoic acid by the action of thionyl chloride. The resultingphenyl carboxamido acetylene 16.9 is reacted with the amino acid 16.4 inthe presence of acetic anhydride. The acetal of the resultingintermediate pyrrole is hydrolyzed with 80% aqueous acetic acid to yield16.10. Condensation of 16.10 with the dianion of ethyl acetylacetatefollowed by reduction of the carbonyl moiety and hydrolysis of the acidester yields the pyrrole 16.11. The protecting group of 16.11 is removedwith trifluoroacetic acid in dichloromethane to afford the unmaskedaniline 16.12, which is subsequently reductively alkylated with theprotected phosphonoacetaldehyde 16.16 to afford the desired Atorvastatinphosphonate conjugate 16.17. The phosphonoacetaldehyde 16.16 can beobtained from the commercially available phosphonodichloridate 16.13 byreaction with an excess of phenol and a suitable base, hydrolysis to themonophenol 16.14, coupling with the isopropyl ester of alanine, followedby ozonolysis and reductive workup.

For the compounds substituted at the R³³ position, the method ofsynthesis is outlined as follows:

The synthesis of intermediate 16.4 is described in U.S. Pat. No.4,681,893 (column 4, line 50). Compound 16.4 is reacted according to theprocedure disclosed in U.S. Pat. No. 4,681,893 with anacetylenecarboxamide of the general structure 16.19, which can beobtained by the reduction of the nitro group of an ortho, meta or paranitrophenylpropynoic acid phenylamide of general structure 16.18 with areagent such as stannous chloride in a solvent such as methanol or DMF,followed by protection of the amine moiety with di-t-butylcarbonate inDMF, to yield compound 16.20 after mild aqueous hydrolysis of the acetalmoiety. Condensation of 16.20 with the dianion of ethyl acetylacetatefollowed by reduction of the carbonyl moiety and hydrolysis of the acidester yields the pyrrole 16.21, which is then treated with an acid suchas trifluoroacetic acid in an appropriate anhydrous aprotic solvent todeprotect the masked aniline function to yield compound 16.22. Thecompound 16.22 is then treated with an aldehyde of general structure16.23. The reductive alkylation is effected with the addition of areducing agent such as sodium cyanoborohydride, or by catalytichydrogenation with a catalyst such as palladium on charcoal in a solventsuch as ethanol, methanol, ethyl acetate, or DMF to afford the desiredcompound of general structure 16.24.

In addition, the synthesis of specific compounds of the invention isdescribed below.

The commercially available phenylpropynoic acid 16.25 is converted toits acid chloride by the action of thionyl chloride. The resulting acylchloride 16.26 is reacted with aniline to afford the carboxamide 16.27.The nitro group of 16.27 is reduced to furnish an intermediate anilinethat is then protected through the action of di-t-butylcarbonate in asolvent such as DMF. The resulting acetylene 16.28 is then reacted withamino acid 16.4 in the presence of acetic anhydride, followed by thehydrolysis of the acetal function with aqueous acetic acid to yield thealdehyde 16.29. Condensation of 16.29 with the dianion of ethylacetylacetate followed by reduction of the keto moiety and hydrolysis ofthe acid ester yields the pyrrole 16.30. The t-butoxycarbonyl group of16.30 is removed with trifluoroacetic acid in a solvent such asdichloromethane and the resulting aniline 16.31 with thephosphonoaldehyde 16.16 to yield the Atorvastatin phosphonate conjugate16.32.

Example 17 Preparation of Representative Compounds of the Invention

Representative compounds of the invention such as shown above, can bemade according to the following method.

Preparation of analog 17.1 is shown above. A generic phosphonatebis-ester can be prepared as demonstrated above and the substituents atphosphorus can be manipulated according to transformations shown herein.The synthesis of specific compound of the invention 17.5 is also shown.The dianion of (2-oxo-propyl)-phosphonic acid diethyl ester is generatedby treatment with over two equivalents of lithium diisopropylamide atlow temperature, and the 17.4 (prepared according to Roth et al., J.Med. Chem., 34:357 (1991)) is added. The isomer with the desiredstereochemistry is isolated by chromatography.

An example of the synthesis of an additional compound of the invention,17.6, is depicted above. A Sonagashira coupling (see Stang, P. J. andDiederich, F., “Metal Catalyzed Cross Coupling Reactions,” Wiley-VCH,Weinheim (1988)) is used to attach the phosphonate moiety. The requisiteacetylene is made by heating 5-chloro-1-pentyne with triethylphosphitein a solvent such as toluene (or other Arbuzov reaction conditions; seeEngel, R., “Synthesis of Carbon-phosphorus Bonds,” CRC press (1988)),and the aryl bromide by the same route as described for otheratorvastatin analogs (Roth et al., J. Med. Chem., 34:357 (1991)),starting from 2-bromo-4-fluorobenzaldehyde.

Example 18 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as discussedbelow.

The phosphorus containing thiazolidinedione derivative 18.3 issynthesized from parent compounds by alkylation. The parent compound18.1 is obtained by the procedure as described in U.S. Pat. No.4,572,912. The attachment of the phosphonate linkage to the phenolic OHof 18.1 to give compounds of formula 18.3 is shown. Compound 18.1 isdissolved in a suitable aprotic solvent such as, DMF and is then treatedwith the phosphonate reagent (A⁰) bearing a leaving group, for example,bromine, mesyl, tosyl, or trifluoromethanesulfonyl, in the presence of asuitable organic or inorganic base.

Specific compounds of the invention can be prepared as follows:

A solution of 18.4 in DMF is treated with cesium carbonate and oneequivalent of (trifluoromethanesulfonyloxy)methylphosphonic acid diethylester 18.5, to give troglitazone-phosphonate 18.6. The linkage is amethylene group as shown. Using the above procedure but employing adifferent 18.1 and phosphonate reagents 18.2, the corresponding products18.3 bearing different substituents and linking groups can be obtained.

The preparation of phosphorus containing thiazolidinedione derivative ofanother type is shown below.

The parent compound 18.7 is obtained by the procedure as described inU.S. Pat. No. 4,572,912. The phenolic OH and thiazolidinedione unit areprotected with suitable protecting group, for example SEM group, and thehydroxyl group at C4 position of chroman alcohol analogs is generated byreduction of the carbonyl group, using suitable reducing agent, forexample sodium borohydride. The alcohol 18.8 is then treated withsuitable chloroformate ester, for example, phenyl chloroformate orp-nitrophenyl chloroformate, or carbonate, such asbis(p-nitrophenyl)carbonate, to generate an active carbonate. Theresulting active carbonate is reacted with phosphonate reagents bearingamino group 18.9, and subsequent deprotection of protecting groupsproduces the phosphonates 18.10.

Another specific compound of the invention can be prepared as follows. Asolution of 18.11 in THF is treated with diisopropylethylamine and twoequivalent of 2-(trimethylsilyl)ethoxymethyl chloride to protect thephenolic OH and thiazolidinedione unit. A solution of the protectedproduct in methanol is then reduced using sodium borohydride to obtainthe alcohol 18.12. The alcohol 18.12 is treated with phenylchloroformate to provide phenyl carbonate, which is reacted with2-aminoethylphosphonate diethyl ester 18.13, to obtain the protectedphosphonate derivative. The protected phosphonate derivative isdeprotected by tetrabutylammonium fluoride in THF to result 18.14. Usingthe above procedure, but employing a different 18.7 and phosphonatereagents 18.9, the corresponding products 18.10 bearing differentsubstituents and linking groups can be obtained.

The preparation of phosphorus containing a thiazolidinedione derivativeof type 18.10 is illustrated below. Thiazolidinedione with phosphoruscontaining moiety 18.16 is generated by the alkylation ofthiazolidinedione 18.15 in a suitable aprotic solvent such as DMF 18.15is then treated with the phosphonate reagent 18.2 bearing a leavinggroup, for example, bromine, mesyl, tosyl, or trifluoromethanesulfonyl,in the presence of a suitable organic or inorganic base. Compound 18.16is then reacted with benzaldehyde 18.17 with protected phenol at thepara position.

The protecting group R⁸⁸ can be any protecting group for phenolic OH,for example, alkoxyalkyl groups, such as the methoxymethyl group;aralkyl groups, such as the benzyl group; the 2-tetrahydropyranyl group;and acyl groups, such as the acetyl or benzoyl groups, preferably benzylgroup. The reaction is carried out in an aprotic solvent, such astoluene, at an elevated temperature, such as the reflux temperature ofthe solvent, and in one embodiment in the presence of a suitablecatalyst, such as piperidinium acetate or benzoate. The water producedin the reaction can be removed from the reaction mixture, for example,by means of a Dean and Stark apparatus.

The reduction of 18.18 to 18.19 is accomplished by catalytic reductionwith suitable catalysts, such as palladium on carbon catalysts, e.g., a10% palladium on charcoal catalyst. (U.S. Pat. No. 6,288,095) Thecoupling of 18.19 with chroman alcohol homolog 18.20, which is obtainedby the procedure described in J. American Oil Chemical Society, 51:200(1974) or in U.S. Pat. No. 4,572,912 yields 18.10. The alcoholicfunctional groups are suitably protected as described in U.S. Pat. No.4,572,912 using Mitsunobu condition.

For example, specific compounds of the invention can be prepared asfollows:

A solution of 18.15 in DMP is treated with sodium hydride and oneequivalent of (trifluoromethanesulfonyloxy)methylphosphonic acid diethylester 18.5 to give thiazolidinedione-phosphonate 18.21 in which thelinkage is a methylene group as shown. The thiazolidinedione-phosphonate18.21 is then reacted with the benzaldehyde 18.22 bearing benzyloxysubstituent in toluene in reflux condition in the presence of catalyticpiperidinium acetate with Dean-Stark apparatus, which results in 18.23.The reduction of 18.23 in dioxane by catalytic hydrogenation in thepresence of 10% palladium on charcoal provides 18.24. The reactionbetween 18.24 and chroman alcohol analogs 18.25 in the presence ofdiethyl azodicarboxylate and triphenylphosphine followed by deprotectionof SEM group by TBAF provides 18.26. Using the above procedure, butemploying different chroman alcohol analogs and phosphonate reagents18.5 the corresponding products 18.26 bearing different substituents andlinking groups can be obtained.

Example 19 Preparation of Representative Compounds of the Invention

Synthesis of representative compounds of the invention can be conductedas described herein.

The phosphonate ester of type 19.5 is synthesized by the couplingbetween the aldehyde 19.3, which is obtained as described in U.S. Pat.No. 6,288,095, and thiazolidinedione 19.2 bearing phosphonate group(A⁰). A solution of thiazolidinedione 19.1 in a suitable aproticsolvent, for example DMF, is treated with the phosphonate reagent (A⁰)bearing a leaving group, for example, bromine, mesyl, tosyl, ortrifluoromethanesulfonyl, in the presence of a suitable organic orinorganic base.

The reaction between 19.2 and the aldehyde 19.3 is carried out in anaprotic solvent, such as toluene, at an elevated temperature, such asthe reflux temperature of the solvent, and in one embodiment in thepresence of a suitable catalyst, e.g., piperidinium acetate or benzoate.In one embodiment, the water produced in the reaction can be removedfrom the reaction mixture, for example, by means of a Dean and Starkapparatus.

The reduction of 19.4 to 19.5 is accomplished by either catalyticreduction with suitable catalysts, such as palladium on carboncatalysts, e.g., a 10% palladium on charcoal catalyst, or the use of ametal/solvent reducing system, such as magnesium in methanol (U.S. Pat.No. 6,288,095).

For example, specific compounds of the invention can be prepared bytreating a solution of 19.1 in DMF with sodium hydride and oneequivalent of (trifluoromethanesulfonyloxy)methylphosphonic acid diethylester to give thiazolidinedione-phosphonate 19.7 in which the linkage isa methylene group. The thiazolidinedione-phosphonate 19.7 is thenreacted with the aldehyde 19.8 in toluene, in reflux conditions, in thepresence of catalytic piperidinium acetate with Dean-Stark apparatus19.9 results. The reduction of 19.9 in dioxane by catalytichydrogenation in the presence of 10% palladium on charcoal provides19.10.

Using this procedure, but employing different aldehyde 19.3 andphosphonate reagents, the corresponding products 19.5 bearing differentsubstituents and linking groups can be obtained.

Example 20 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as follows:

The preparation of phosphonate and phosphonamidate conjugates ofthiazolidinedione derivatives of type 20.7 is shown above. These typesof compounds are obtained by the reactions described in U.S. Pat. No.6,288,095 using 20.1 bearing a suitable substituent, for example nitroand cyano groups, which can be converted to the functional group tointroduce a phosphorus containing moiety. The substituent of 20.5 or20.6 is converted to adequate functional group, such as an amino oraldehyde group, either during the reduction of benzylidenethiazolidinedione or by a separate step. The attachment of phosphonatemoieties is accomplished by suitable reduction conditions. Thephosphonate group bearing moiety is attached by reductive aminationusing a suitable reducing agent, such as sodium cyanoborohydride, insuitable solvents, such as dichloroethane or methanol, under acidiccondition using an acid, such as acetic acid.

For example, the synthesis of specific compounds of the invention isdescribed below.

The nitropyridine derivative 20.8 is converted to 20.9 according to aseries of the reactions described in U.S. Pat. No. 6,288,095. Thereduction of the nitro group of 20.9 occurs during reduction of thebenzylidenethiazolidinedione under catalytic hydrogenation conditionswith a 10% palladium on charcoal catalyst. A phosphonate moiety is thenintroduced to the amino group of 20.10 by reductive amination indichloroethane using 2-oxoethylphosphonic acid diethyl ester 20.11 andsodium cyanoborohydride and acetic acid. The resulting secondary amine20.12 (R═H) may be converted to the corresponding tertiary amine 20.12(R=Me) by reductive amination using formaldehyde and sodiumcyanoborohydride.

Another example for the synthesis of specific compounds of the inventionis shown below.

The pyridine 20.13 bearing a cyano group is converted to 20.14 accordingto a series of the reactions described in U.S. Pat. No. 6,288,095. Thereduction of the cyano group of 20.14 to the corresponding aldehyde20.15 is accomplished by DIBAL. Phosphonate moiety is then introduced tothe aldehyde group of 20.15 by reductive amination procedure using2-aminoethylphosphonic acid diethyl ester 20.16 and sodiumcyanoborohydride and acetic acid. The resulting secondary amine 20.17(R═H) may be converted to the corresponding tertiary amine 20.17 (R=Me)by reductive amination using formaldehyde and sodium cyanoborohydride.

The synthesis of a specific compound of the invention, a conjugate of20.7 with carbamate linker, is shown below. The aldehyde bearing 20.16is further reduced with sodium borohydride, and the correspondingalcohol 20.18 is treated with phenyl chloroformate providing the phenylcarbonate 20.19. Treatment of 20.19 with phosphonate reagents 20.16bearing amino group generates 20.21.

Example 21 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as describedbelow.

The synthesis of representative compounds of the invention can beachieved via a variety of routes. For example, the protected core ofrosiglitazone can be assembled first, followed by addition of thepro-drug group.

The preparation of a specific example, compound 21.6, in which X is C═O,is shown above. Oxidation of the benzylic position of2-chloro-5-methylpyridine according to the procedure of Collie, J. Chem.Soc., 71:653 (1897) provides compound 21.1. Protection of the carboxylicacid followed by reaction with compound 21.3 prepared as described inCantello et al., J. Med. Chem., 37:3977 (1994) gives compound 21.4.Deprotection of the ester followed by coupling of the acid 21.5 to anamine carrying the phosphonate moiety provides compound 21.6.

Detailed synthesis of specific compounds of the invention is shownbelow.

The starting material, 2-chloro-5-methylpyridine (commerciallyavailable), can be oxidized at the benzylic position using potassiumpermanganate to provide compound 21.1 (Collie, J. Chem. Soc., 71:653(1897)). Carboxylic acid 21.1 is blocked with a bulky protecting groupsuch as t-butyl to form 21.2. The 2-chloro-pyridine moiety undergoes anaddition-elimination reaction with amine 21.3 (described in Cantello etal.) to give compound 21.4. Removal of the ester protecting group usingtrifluoroacetic acid (TFA) (Greene, “Protective Groups in OrganicSynthesis,” Wiley-Interscience, (1999)) provides the precursor forattachment of the pro-drug. Standard peptide coupling conditions providecompound 21.7.

Example 22 Preparation of Representative Compounds of the Invention

Synthesis of a representative compound of the invention is shown below.

The above route is similar to that illustrated in Example 20. An exampleof the preparation of specific compounds of the invention is describedbelow.

The starting material, 2-chloro-4-methylpyridine (commerciallyavailable), can be oxidized at the benzylic position using potassiumpermanganate to provide compound 22.1 (Collie, J. Chem. Soc., 71:653(1897)). Carboxylic acid 22.1 is blocked with a bulky protecting group,such as t-butyl, to form 22.2. The 2-chloro-pyridine moiety undergoes anaddition-elimination reaction with amine 22.3 (described in Cantello etal., J. Med. Chem., 37:3977 (1994)). Removal of the ester protectinggroup using TFA (Greene, T., “Protective Groups in Organic Synthesis,”Wiley-Interscience, (1999)) provides the precursor for attachment of thepro-drug 22.7. Standard peptide coupling conditions provide compound22.5.

A variety of linking groups can be utilized on the pyridinium ring. Forexample, the use of 6-chloro-pyridine-3-carbaldehyde allows forattachment of the phosphonate containing group via reductive amination.In this case, the attachment point would be a carbon (X═C).

Example 23 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be made according to thegeneral route outlined below:

The preparation of compound 23.1, which is one example of the attachmentof the pro-drug at the 4-phenoxy moiety of R-483, is shown above. Inaddition, a number of salts of the final pro-drug can be prepared.Specifically, a sodium salt may be prepared by addition of NaOH at thelast step (see WO 01/79202).

Compound 23.1 is prepared by bromination of a β-keto ester at theγ-position. Condensation with 4-allyloxy-3,5-dimethyl-benzamide(prepared according to U.S. Pat. No. 2,912,453; Chem. Abstracts, 4500(1960)) provides compound 23.2. Reduction of the ester followed byconversion of the alcohol to mesylate provides compound 23.3.Displacement of the mesylate by benzo[b]thiophen-4-ol gives compound23.4. Reaction of compound 23.4 with formaldehyde and HBr provides forthe convenient addition of 2,4-thiazolidinedione anion to form compound23.6. Removal of the protecting group, followed by treatment of theliberated phenol in a solvent such as tetrahydrofuran ordimethylformamide with a base such as sodium hydride with addition ofdiethyl phosphonomethyltriflate (prepared according to TetrahedronLett., 27:1477 (1986)) yields the desired phosphonate diester.

The synthesis of specific compounds of the invention is shown below.

The protecting group used for 4-hydroxy-3,5-dimethyl-benzamide is theallyl group (U.S. Pat. No. 2,912,453; see also Chem. Abstracts, 4500(1960)). The synthesis is followed as described above. Removal of theallyl group can be achieved using Wilkinson's catalyst to provide thephenol (Greene, “Protective Groups in Organic Synthesis,”Wiley-Interscience, (1999)). Alkylation of the phenol using diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett.,27:1477 (1986)) yields the desired phosphonate diester 23.7.

Example 24 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be made according to thegeneral route outlined below.

Compound 24.1, 5-(2,4-dioxo-thiazolidin-5-ylmethyl)-2-methoxy-benzoicacid, can be prepared according to U.S. Pat. No. 6,030,990. Acid 24.1can be coupled to a variety of benzyl amines utilizing well-knowncoupling conditions, such as1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide or diethyl cyanophosphatein an organic solvent such as dimethyl sulfoxide orN,N-dimethylformamide to produce amide 24.4. The handle on compound 24.4can be utilized for attachment of the pro-drug.

4-(aminomethyl)phenol from Apin Chemicals can be used as the couplingpartner to the acid 24.1 to provide phenol 24.4. Compound 24.4 can betreated in a solvent such as tetrahydrofuran or dimethylformamide with abase such as sodium hydride. When bubbling ceases, diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett.,27:1477 (1986)) is added, yielding the desired phosphonate diester 24.5.

The synthesis of compound 24.6 is shown below.

Preparation of 24.1 can be achieved according U.S. Pat. No. 6,030,990.Coupling of 3-(aminomethyl)phenol from Apin Chemicals to the acid 24.1using common coupling reagents provides phenol 24.6. Treatment of 24.6in a solvent such as tetrahydrofuran or dimethylformamide with a basesuch as sodium hydride followed by addition of diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett.,27:1477 (1986)) after cessation of bubbling, yields the desiredphosphonate 24.7, e.g., 24.9.

Example 25 Preparation of Representative Compounds of the Invention

Compounds of the invention can be made according to the general routeoutlined below.

2-(4-Hydroxyphenyl)ethanol is first protected on the phenolic hydroxylgroup to provide compound 25.1. The primary alcohol is then turned intoa good leaving group and is displaced using compound 25.1 (as disclosedin U.S. Pat. No. 6,531,622). The phenol of the fully-protected compound25.4 is deprotected and alkylated, and the ester is saponified toprovide compound 25.5.

The detailed synthesis of a representative compound of the invention isshown below.

2-(4-Hydroxyphenyl)ethanol is first protected on the phenolic OH groupwith a tert-butyldimethyl silyl group to provide compound 25.1. Turningthe primary alcohol into a suitable leaving group is achieved usingmesyl chloride in dichloromethane and a teriary amine such astriethylamine as a base. Displacement of the mesylate is achieved usingethyl (S)-2-ethoxy-3-(4-hydroxyphenyl)propanoate 25.3 as described inU.S. Pat. No. 6,531,622. Removal of the silyl group with a source offluoride ion such as tetrabutylammonium fluoride, liberates the phenol,which can then react with diethyl phosphonomethyltriflate (preparedaccording to Tetrahedron Lett., 27:1477 (1986)) in a solvent such as DMFusing a base such as sodium hydride. Finally, the carboxylate ester isselectively hydrolyzed by treatment with lithium hydroxide to providepro-drug 25.6.

Example 26 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as follows:

The5-(4-{2-[5-(1-Hydroxy-ethyl)-pyridin-2-yl]-ethoxy}-benzyl)-thiazolidine-2,4-dionecan be prepared according to the procedure reported in Tanis et al., J.Med. Chem., 39:5053 (1996). Compound 26.1 can be treated in a solventsuch as tetrahydrofuran or dimethylformamide with a base such as sodiumhydride. When bubbling ceases, diethyl phosphonomethyltriflate (preparedaccording to Tetrahedron Lett., 27:1477 (1986)) is added, yielding thedesired phosphonate diester 26.2, e.g., 26.3.

Synthesis of another representative compound of the invention is shownabove. Preparation of 26.4 can be achieved according to Tanis et al., J.Med. Chem., 39:5053 (1996). Reductive amination of compound 26.4 usingan amino phosphonate under sodium cyano borohydride or sodium triacetoxyborohydride in solvents such as methanol or THF yields product 26.5,e.g., 26.6, in a few hours. A number of amino diethyl phosphonates areavailable from Fluka.

Example 27 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be made according to thegeneral route outlined below:

The preparation of analog 27.8 is described herein. A genericphosphonate bis-ester can be prepared as demonstrated above. Thesubstituents at phosphorus can be manipulated according totransformations described herein.

An example of the synthesis of specific compounds of the invention isshown below:

The synthesis begins with the formation of silyl enol ether ofmethylacetoacetate (available from Aldrich) using TMSCl and LDA asdescribed in Jullien et al., Tetrahedron Lett., 23(47):4943 (1982) toform compound 27.1. Bromination under the conditions reported by Chan etal., J. Chem. Soc. Chem. Commun., 578 (1979) yields4-bromo-3-oxo-butyric acid methyl ester 27.2. Arbuzov reaction of thebromide 27.2 with triethylphosphite as reported by Yuan et al.,Heteroatom Chemistry, 13(2):153 (2002) provides diethyl phosphonate27.3. Addition of ester 27.3 to bakers' yeast in water yields4-(diethoxyphosphoryl)-3-R-hydroxybutanoic acid methyl ester 27.4 asdescribed by Yuan et al.

Silylation of the newly generated secondary alcohol using TBSCl andimidazole followed by selective removal of the methyl ester protectinggroup as described in Greene, T., “Protective Groups in OrganicSynthesis,” Wiley-Interscience (1999) provides compound 27.5. Carboxylicacid 27.5 is treated with methyl chlorocarbonate and triethylamine togive a mixed anhydride that is then converted to compound 27.6 byreacting with methylidenetriphenylphosphorane according to the methoddescribed in Konoike et al., J. Org. Chem., 59:7849 (1994).

A Wittig reaction between compound 27.6 and aldehyde 27.9 (preparedaccording to Watanabe et al., Bioorg. & Med. Chem., 5:437 (1997))provides the olefin analog 27.11. Removal of the TBS protecting groupwith HF in MeCN followed by stereoselective chelation-controlledreduction with Et₂BOMe and sodium borohydride in THF: MeOH gives thedesired phosphonate 27.12.

Example 28 Preparation of Representative Compounds of the Invention

The general route outlined below can be used to prepare representativecompounds of the invention.

Pro-drugs such as 28.11 can be prepared as demonstrated above (see alsoWatanabe et al., Bioorg. & Med. Chem., 5(2):437 (1997)).

More specifically, preparation of a diethyl phosphonomethyl pro-drug28.13 is as follows:

Protection of the phenolic group of 4-fluoro-2-hydroxybenzaldehyde(available from Apollo chemicals) according to methods described indescribed in Greene, “Protective Groups in Organic Synthesis,”Wiley-Interscience (1999) provides compound 28.1. Knoevenagel reactionof compound 28.1 with ethyl isobutyrylacetate provides the unsaturatedketoester. Cyclocondensation of 28.2 with S-methylisothiourea hydrogensulfate followed by dehydrogenation with DDQ affords the pyrimidine ringin 28.3. The thioether is oxidized with m-chloroperbenzoic acid to givesulfonylpyrimidine 28.4. Displacement of the sulfone with MeNH₂ in MeOHfollowed by treatment with methanesulfonyl chloride gives theN-methanesulfonyl amino derivative 28.5.

Reduction of the ester in 28.5 with DIBAL-H followed by TPAP oxidationafforded the corresponding aldehyde 28.6. The desired side chain isattached by Wittig reaction of aldehyde 28.6 with the optically activeylide 28.7 (prepared according to Konoike et al., J. Org. Chem., 59:7849(1994)).

Deprotection of 28.8 with HF in MeCN and stereoselectivechelation-controlled reduction with Et₂BOMe and NaBH₄ in THF:MeOHfollowed by removal of the benzyl protecting group gives compound 28.9.

If the hydrogenation conditions necessary for removal of the benzylgroup reduce the trans olefin, an exchange of the phenol protectinggroup can be done on 28.6. The benzyl protecting group may be exchangedfor an acid labile group such as TMSE or DPM which can be removedsimultaneously with the TBS removal step. Ultimately, the benzylprotecting group may be removed on compound 28.6 and the phenol may becarried forward without protection.

Attachment of the phosphonate pro-drug is achieved by suspending 28.9 inan anhydrous solvent and addition of a base such as cesium carbonate,followed by addition of diethyl phosphonomethyltriflate (preparedaccording to Tetrahedron Lett., 27:1477 (1986)), yielding the desiredcompound 28.12. Removal of the methyl ester protecting group generatesthe free carboxylic acid, from which a variety of salts such as thatshown may be prepared.

Example 29 Preparation of Representative Compounds of the Invention

The general route outlined below can be used to prepare representativecompounds of the invention.

Synthesis of pro-drugs described herein follows the literature (Watanabeet al., Bioorg. & Med. Chem., 5(2):437 (1997)). The starting materials,compound 29.1, is treated with methylamine followed by 2-chloroethanesulfonyl chloride (available from Aldrich) to provide compound 29.2.Addition of the phosphonate moiety via an Arbuzov reaction yields thepro-drug 29.3.

Subsequent reduction of the ester group with DIBAL-H followed by TPAPoxidation gives the corresponding aldehyde. Formation of the heptanoate29.6 using the optically active 29.5, as discussed previously, via aWittig reaction yields the desired product 29.6. Removal of the TBSprotecting group using HF in MeCN, and the stereoselectivechelation-controlled reduction with Et₂BOMe and NaBH₄ provides compound29.7. Release of the methyl ester protecting group under basicconditions provides the free carboxylic acid, from which a variety ofsalts such as shown may be prepared.

Specific compounds of the invention may be prepared as follows:

Example 30 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared according tothe following methods.

Synthesis of Compound 30.5

To a solution of 2-(diethylphosphono)butyric acid (183 mg, 0.87 mmol) inbenzene (5 mL), triethylamine (0.20 mL, 1.45 mmol) and diethylchlorophosphate were added, followed by 4-pyrrolidinopyridine (162 mg,1.1 mmol). The resulting mixture was stirred for 30 minutes when 25.4(200 mg, 0.36 mmol) was added. After 18 hours the reaction mixture waspartitioned between ethyl acetate and 1N HCl. After separating thelayers, the organic extract was washed with water, saturated aqueoussodium bicarbonate, and saturated brine, and then dried over anhydroussodium sulfate. The solvent was removed to produce an oil that waspurified by silica gel chromatography, eluting with ethylacetate/hexanes (gradient 1/3 to 1/1), giving 247 mg of compound 30.5 asa white foam.

MS m/z (M+H)+ 743.42;

1H NMR (300 MHz, CDCl₃) δ 0.072-0.094 (m, 12H), 0.87-0.89 (m, 21H),1.27-1.46 (m, 12H), 1.61-1.88 (m, 5H), 2.32-2.59 (m, 5H), 2.96-3.10 (M,1H), 4.05-4.18 (m, 4H), 4.25-4.30 (m, 1H), 4.47-4.68 (m, 2H), 5.40-5.43(m, 1H), 5.45-5.48 (m, 1H), 5.84 (dd, 1H, J=5.9, 9.3 Hz), 5.96 (d, 1H,J=9.7 Hz).

Synthesis of Compound 30.7

To a solution of 30.5 (240 mg, 0.32 mmol) in tetrahydrofuran cooled to0° C., acetic acid (0.31 mL, 5.39 mmol) was added followed bytetraethylammonium fluoride dihydrate (598 mg, 3.23 mmol). Afterstirring 18 hours at room temperature, the solvents were removed underreduced pressure and the residue was partitioned between dichloromethaneand saturated aqueous sodium bicarbonate. After separating the layers,the organic extract was washed with saturated aqueous sodium bicarbonateand saturated brine, and then dried over anhydrous sodium sulfate. Thesolvent was removed to produce an oil that was purified by silica gelchromatography, eluting with chloroform/methanol (gradient 98/2 to95/5), to give the compound 30.7 as a white foam (44 mg). MS m/z (4+H)+515.18

1H NMR (300 MHz, CDCl₃) δ 0.90 (d, 3H, J=7.0 Hz), 1.26-1.47 (m, 9H),1.52-1.60 (m, 5H, 1H, D2O exchangeable), 1.71-1.99 (m, 4H), 2.31-2.45(m, 2H), 2.52-2.65 (m, 2H), 2.70-2.81 (m, 1H), 2.90-3.13 (m, 1H),3.60-3.64 (m, 0.5H, D2O exchangeable), 3.99-4.32 (m, 5.5H, 0.5H, D2Oexchangeable), 4.38-4.56 (m, 1H), 4.60-4.77 (m, 1H), 5.47-5.55 (m, 1H),5.56 (bs, 1H), 5.85-5.93 (m, 1H), 5.96-6.01 (m, 1H).

Synthesis of Compound 30.8

To a solution of lactone 25.7 (41 mg, 79.7 μmol) in dioxane (1 ml) anddeionized water (0.5 ml), 0.1N NaOH (0.77 ml, 77 μmol) was added. After30 minutes at room temperature, the sample was lyophilized overnight,giving 69 mg of a white powder that was shown by HPLC to be a 63/34mixture of 30.8/30.7.

MS m/z (M+H)+ 515 (30.7), 533 (open lactone), 555 (30.8) 31P NMR (121.7MHz, CDCl₃/external H3PO4): δ 26.3-28.7 (m) HPLC (Sphereclone 5μ, H2O:MeCN, 20 min liner gradient from 10-90% MeCN, 1.0 mL/m1n)-30.8 ret. time5.17, 63%; 30.7 ret. time 11.96, 33.7%.

Example 31 Preparation of Representative Compounds of the Invention

The synthesis of Ospemifene, 31.1 is described in WO01/36360. Compound31.1 is treated with a dialkylphosphonoalkyltrifluoromethylsulphonate ina solvent such as pyridine or a non basic solvent such asdichloromethane containing a base such as triethylamine to furnish theether of 31.2. The alkyl groups are removed from the phosphonate moietywith trimethylsilylbromide in a solvent such as DMF or acetonitrile tofurnish compound 31.3, which then can be converted to the desiredprodrug 31.4 using the methods of phosphonate ester and amidateformation described below.

This example describes the synthesis of a compound 31.11, a particularmember of the general class of compounds described by the structure31.4. Compound 31.1 is treated withdiethylphosphonomethyltrifluorosulphonate, 31.7, in pyridine to yieldthe ether 31.8. Compound 31.8 is treated with trimethylsilylbromide inacetonitrile to yield the free phosphonic acid 31.9. Compound 31.9 isthen treated with dicyclohexylcarbodiimide and phenol in DMF to yieldthe monophenol ester 31.10, which is then condensed with theisopropylester of alanine using aldrithiol and triphenylphosphine in DMFto yield the desired prodrug 31.11

Example 32 Preparation of Representative Compounds of the Invention

The synthesis of compound 32.5 is described in U.S. Pat. No. 3,576,883.Compound 32.5 is treated with one equivalent of an acyl chloride of adialkylphosphonoalkylcarboxylic acid in a solvent such as pyridine or anon basic solvent such as dichloromethane containing a base such astriethylamine to furnish the monoester of 32.5, compound 32.6. The alkylgroups are removed from the phosphonate moiety withtrimethylsilylbromide in a solvent such as DMF or acetonitrile tofurnish compound 32.7, which then can be converted to the desiredprodrug 32.3 using the methods of phosphonate ester and amidateformation described below.

This example describes the synthesis of a compound 32.14, a particularmember of the general class of compounds described by the structure32.3. Compound 32.5 is treated with diethylphosphonomethylchloroformate,32.10, in pyridine to yield the monoester 32.11. Compound 32.11 istreated with trimethylsilylbromide in acetonitrile to yield the freephosphonic acid 32.12. Compound 32.12 is then treated withdicyclohexylcarbodiimide and phenol in DMF to yield the monophenol ester32.13, which is then condensed with the isopropylester of alanine usingaldrithiol and triphenylphosphine in DMF to yield the desired prodrug32.14.

The phosphonate esters of type 32.4 are synthesized from thesulfonylurea derivatives by alkylation and converted to the finalconjugates. Sulfonylurea derivatives are either commercially availableor obtained by the known procedure, for example, as described in U.S.Pat. No. 3,454,635, U.S. Pat. No. 3,669,966, and U.S. Pat. No.4,379,785.

The attachment of the phosphonate linkage to the nitrogen of sulfamidogroup is shown to give compounds of the invention. Sulfonylureaderivative 32.9 is dissolved in a suitable aprotic solvent, for example,DMF, with the phosphonate reagent (A⁰), bearing a leaving group, forexample, bromine, mesyl, tosyl, or trifluoromethanesulfonyl, in thepresence of a suitable organic or inorganic base. For example, asolution of 32.1 in DMF is treated with sodium hydride and oneequivalent of (trifluoromethanesulfonyloxy)methylphosphonic acid diethylester 32.11 to give the analog 32.12 in which the linkage is a methylenegroup. Using the above procedure but employing different sulfonylureaderivatives 32.9 in place of 32.1 and phosphonate reagents 32.10 inplace of 32.11 the corresponding products 32.4 bearing differentsubstituents and linking groups can be obtained.

Some phosphonates of type 32.5, where Z is oxygen or sulfur, can beprepared. The sunfonamide 32.13 is reacted with isocyanate 32.14 bearinga suitable phosphorus containing substituent, (A⁰). The isocyanatereagent 32.14 is obtained by Curtius rearrangement reaction from thecorresponding carboxylic acid, as explained in Organic Reactions, 1946,3, 337-449. Attachment of the phosphorus containing moiety to the Zgroup, such as hydroxyl or thiol group, is accomplished by alkylationprocedure in a suitable aprotic solvent, for example, DMF, with thephosphonate reagent 32.10, bearing a leaving group, for example,bromine, mesyl, tosyl, or trifluoromethanesulfonyl, in the presence of asuitable organic or inorganic base.

For example, a solution of 32.15 in DMF is treated with 2 equivalent ofsodium hydride and one equivalent of(trifluoromethanesulfonyloxy)methylphosphonic acid diethyl ester 32.11to provide 32.16 in which the linkage is a methylene group. Thecarboxylic acid of 32.16 is treated with oxalyl chloride, followed bythe reaction with sodium azide and pyrolysis to give the isocyanate32.17. The sulfonylurea derivative 32.19 is obtained by the reaction ofisocyanate 32.17 with the sulfonamide 32.18, which is obtained by theprocedure of U.S. Pat. No. 3,669,966. Using the above procedure butemploying different sulfonamide 32.13, R⁴ bearing hydroxy or thiolgroup, and phosphonate reagents 32.10 the corresponding products 32.5,where Z is oxygen or sulfur, bearing different R³, R⁴ and linking groupscan be obtained.

The preparation of sulfonylurea derivatives bearing phosphoruscontaining moiety of type 32.5, where Z is carbamate linker, is shown.These types of compounds are obtained by the coupling of sunfonamide32.13 using isocyanate 32.20 bearing a suitably protected alcohol, suchas benzyl group. The isocyanate reagent 32.20 is obtained byaforementioned rearrangements from the corresponding carboxylic acid.After the protective group of 32.21 is removed by a suitable method, thealcohol group is treated with suitable chloroformate ester, for examplephenyl chloroformate or p-nitrophenyl chloroformate, or carbonate, suchas bis(p-nitrophenyl)carbonate to generate an active carbonate. Theresulting active carbonate is reacted with phosphonate reagents bearingamino group to produce the phosphonates of type 32.5, where Z iscarbamate linker.

For example, the carboxylic acid of 32.23 is converted to the isocyanate32.24 by Curtius rearrangement of the acyl azide, which is produced fromthe carboxylic acid 32.23 through acyl chloride and acyl azide. Theisocyanate 32.24 is treated with the anion of sulfonamide 32.18, whichis generated with sodium hydroxide as described. The benzyl protectinggroup of 32.25 is removed by catalytic hydrogenation using 10% Palladiumon charcoal as a catalyst, and the resulting alcohol is treated withphenyl chloroformate to provide phenyl carbonate, which is reacted with2-aminoethylphosphonate diethyl ester 32.26, to obtain sulfonylureaderivative 32.27. Using the above procedure but employing differentsulfonamide 32.13, isocyanate 32.20 and phosphonate reagents 32.22 thecorresponding products 32.5, where Z is carbamate, bearing different R³,R⁴ and linking groups can be obtained.

Phosphonates of type 32.5, where Z is nitrogen, are prepared. Thesetypes of compounds are obtained by the coupling of sunfonamide 32.13using isocyanate 32.28 bearing R⁴⁴ with a suitably protected aminesubstituent. The phosphonate group bearing moiety is attached byreductive amination using a suitable phosphonate reagent 32.30 bearingaldehyde group with reducing agent, such as sodium cyanoborohydride, insuitable solvents, such as dichloroethane or methanol, in the presenceof an acid, such as acetic acid. The resulting secondary amine 32.5(R⁹⁹═H) may be converted to the corresponding tertiary amine 32.5(R⁹⁹=alkyl) by reductive amination.

For example, a solution of 32.31 in THF is treated with oxalyl chloridefollowed by sodium azide and the resulting acyl azide is converted tothe isocyanate 32.32 by heating. A solution of the sulfonamide 32.18,which is obtained as described in U.S. Pat. No. 3,669,966, in DMF istreated with one equivalent of sodium hydride followed by the isocyanate32.32 to generate 32.33. The Boc protecting group is removed bytreatment with trifluoroacetic acid and the resulting amine is treatedwith one equivalent of 2-oxoethylphosphonate diethyl ester 32.34 withsodium cyanoborohydride and acetic acid in dichloroethane to obtain32.35 in which the linkage is an ethylene group and R⁹⁹ is hydrogen asshown in Example 2.3. The resulting secondary amine 32.35 (R⁹⁹═H) isconverted to the corresponding tertiary amine 32.35 (R⁹⁹=Me) byreductive amination with formaldehyde using sodium cyanoborohydride andacetic acid. Using the above procedure but employing differentsulfonylamide 32.13, isocyanate 32.28, and phosphonate reagents 32.30the corresponding products 32.5, where Z is NH or NR⁹⁹, bearingdifferent R³³, R⁴⁴, R⁹⁹, and linking groups can be obtained.

Phosphonate analogs of type 32.6 are synthesized. These types ofcompounds are obtained by the coupling, as described in U.S. Pat. No.3,669,966, of substituted pyrazine carboxylic acid 32.36 bearing amino,hydroxyl, or other substituents, which can convert to appropriatefunctional group for the attachment of phosphonate moiety, for examplecarboxylic ester, with sulfonylurea moiety 32.37. Substituted pyrazinecarboxylic acids are commercially available or may be prepared by themethod described in Ber. 1907, 40, 4850 or in Ber. 1966, 99, 364.Phosphonate moiety is introduced to a substituent on the pyrazine ring,if necessary after conversion of the substituent to a suitablefunctional group bearing substituent, either by alkylation, reductiveamination, or reaction with active carbonate intermediate as describedpreviously.

For example, pyrazine-2,5-dicarboxylic acid mono ester 32.39, which isgenerated by partial hydrolysis, is treated with sulfonylurea 32.40 inthe presence of EDC and HOBt to form the amide 32.41. The carboxylicester of 32.41 is then reduced with LiBH₄ in methanol and the resultingalcohol was treated with phenyl chloroformate to generate the activecarbonate. Treatment of the active carbonate with 2-aminoethylphosphonate diethyl ester 32.26 generates the phosphonate analog 32.42in which the linker is carbamate group. The ester may be treated withDIBAL to generate aldehyde functional group and subsequent reductiveamination produces analog 32.43. Using the above procedures butemploying different pyrazine carboxylic acid 32.36, sulfonulurea 32.37,and phosphonate reagents, the corresponding products 32.6 bearingdifferent linking groups can be obtained.

Phosphonate analogs of type 32.7 are prepared. This type of compound isobtained by the coupling, as described in U.S. Pat. No. 3,669,966, ofsubstituted benzoic acid 32.44 bearing amino, hydroxyl, or othersubstituents, which can convert to appropriate functional group for theattachment of phosphonate moiety with sulfonylurea moiety 32.37.Phosphonate moiety is introduced to a substituent on the aromatic ring,if necessary after conversion of the substituent to a suitablefunctional group bearing substituent, either by alkylation, reductiveamination, or reaction with active carbonate intermediate as describedpreviously. Alternatively, the phosphorus containing moiety is attachedto a substituent of benzoic acid analogs 32.44 and the resulting 32.45is coupled with sulfonylurea moiety.

For example, a solution of 3-chloro-2-hydroxybenzoic acid 32.39 in DMFis treated with cesium carbonate and one equivalent of(trifluoromethanesulfonyloxy)methylphosphonic acid diethyl ester to givethe analog 32.12 in which the linkage is a methylene group as shown inExample 3.2. Using the above procedure but employing benzoic acid 32.44,sulfonulurea 32.37, and phosphonate reagents 32.10, 32.22, or 32.30, thecorresponding products 32.6 bearing different R⁴⁴, R⁶⁶, R⁷⁷, R⁸⁸, andlinking groups can be obtained.

The synthesis of phosphonate analogs of type 32.8 is shown. This type ofcompounds are obtained by the coupling, as described in U.S. Pat. No.4,379,785, of substituted 32.50 bearing amino, hydroxyl, or othersubstituents, which can convert to appropriate functional group for theattachment of phosphorus containing moiety with isocyanate 32.51 bearingsulfonylurea moiety. Alternatively, the phosphorus containing moiety isattached to a substituent of 32.50 and the resulting 32.53 is coupledwith the isocyanate bearing sulfonylurea moiety 32.51. Phosphonatemoiety is introduced to a substituent on 32.50 or 32.53, if necessaryafter conversion of the substituent to a suitable functional groupbearing substituent, either by alkylation, reductive amination, orreaction with active carbonate intermediate as described previously.

For example, 32.54, which is available by the procedure in TetrahedronLett. 2000, 40, 2825, is protected using Boc group and then the silylprotecting group is removed by tetrabutylammonium fluoride, whichresults 32.55. The phosphorus containing moiety is introduced byalkylation using one equivalent of(trifluoromethanesulfonyloxy)methylphosphonic acid diethyl ester 32.11with sodium hydride, and the Boc protecting group is removed usingtrifluoroacetic acid. The reaction of 32.56 with 32.57 in elevatedtemperature produces 32.58 in which the linkage is a methylene group.Using the above procedure but employing 32.50, 32.51, and phosphonatereagents 32.10, 32.22, or 32.30, the corresponding products 32.6 bearingdifferent heterocycles and linking groups can be obtained.

Example 33 Preparation of Representative Compounds of the Invention

The phosphonate esters of type 33.4 are synthesized from thesulfonylurea derivatives by alkylation and converted to the finalconjugates. Sulfonylurea derivatives are either commercially availableor obtained by the known procedure, for example, as described in U.S.Pat. No. 3,454,635, U.S. Pat. No. 3,669,966, and U.S. Pat. No.4,379,785.

Attachment of the phosphonate linkage to the nitrogen of sulfamido groupto gives compounds of formula 33.4. Sulfonylurea derivative 33.9 isdissolved in a suitable aprotic solvent, for example, DMF, with thephosphonate reagent (A⁰), bearing a leaving group, for example, bromine,mesyl, tosyl, or trifluoromethanesulfonyl, in the presence of a suitableorganic or inorganic base. For example, a solution of 33.1 in DMF istreated with sodium hydride and one equivalent of(trifluoromethanesulfonyloxy)methylphosphonic acid diethyl ester 33.11to give the analog 33.12 in which the linkage is a methylene group.Using the above procedure but employing different sulfonylureaderivatives 33.9 in place of 33.1 and phosphonate reagents 33.10 inplace of 33.11 the corresponding products 33.4 bearing differentsubstituents and linking groups can be obtained.

Some phosphonates of type 33.5, where Z is oxygen or sulfur, can beprepared. The sunfonamide 33.13 is reacted with isocyanate 33.14 bearinga suitable phosphorus containing substituent, (A⁰). The isocyanatereagent 33.14 is obtained by Curtius rearrangement reaction from thecorresponding carboxylic acid, as explained in Organic Reactions, 1946,3, 337-449. Attachment of the phosphorus containing moiety to the Zgroup, such as hydroxyl or thiol group, is accomplished by alkylationprocedure in a suitable aprotic solvent, for example, DMF, with thephosphonate reagent 33.10, bearing a leaving group, for example,bromine, mesyl, tosyl, or trifluoromethanesulfonyl, in the presence of asuitable organic or inorganic base.

For example, a solution of 33.15 in DMF is treated with 2 equivalent ofsodium hydride and one equivalent of(trifluoromethanesulfonyloxy)methylphosphonic acid diethyl ester 33.11to provide 33.16 in which the linkage is a methylene group as shown inExample 2.1. The carboxylic acid of 33.16 is treated with oxalylchloride, followed by the reaction with sodium azide and pyrolysis togive the isocyanate 33.17. The sulfonylurea derivative 33.19 is obtainedby the reaction of isocyanate 33.17 with the sulfonamide 33.18, which isobtained by the procedure of U.S. Pat. No. 3,669,966. Using the aboveprocedure but employing different sulfonamide 33.13, R⁴ bearing hydroxyor thiol group, and phosphonate reagents 33.10 the correspondingproducts 5, where Z is oxygen or sulfur, bearing different R³, R⁴ andlinking groups can be obtained.

The preparation of sulfonylurea derivatives bearing phosphoruscontaining moiety of type 33.5 is shown, where Z is carbamate linker.This type of compounds are obtained by the coupling of sunfonamide 33.13using isocyanate 33.20 bearing a suitably protected alcohol, such asbenzyl group. The isocyanate reagent 33.20 is obtained by aforementionedrearrangements from the corresponding carboxylic acid. After theprotective group of 33.21 is removed by a suitable method, the alcoholgroup is treated with suitable chloroformate ester, for example phenylchloroformate or p-nitrophenyl chloroformate, or carbonate, such asbis(p-nitrophenyl)carbonate to generate an active carbonate. Theresulting active carbonate is reacted with phosphonate reagents bearingamino group to produce the phosphonates of type 33.5, where Z iscarbamate linker.

For example, the carboxylic acid of 33.23 is converted to the isocyanate33.24 by Curtius rearrangement of the acyl azide, which is produced fromthe carboxylic acid 33.23 through acyl chloride and acyl azide. Theisocyanate 33.24 is treated with the anion of sulfonamide 33.18, whichis generated with sodium hydroxide. The benzyl protecting group of 33.25is removed by catalytic hydrogenation using 10% Palladium on charcoal asa catalyst, and the resulting alcohol is treated with phenylchloroformate to provide phenyl carbonate, which is reacted with2-aminoethylphosphonate diethyl ester 33.26, to obtain sulfonylureaderivative 33.27. Using the above procedure but employing differentsulfonamide 33.13, isocyanate 33.20 and phosphonate reagents 33.22 thecorresponding products 33.5, where Z is carbamate, bearing different R³,R⁴ and linking groups can be obtained.

Phosphonates of type 33.5, where Z is nitrogen, are prepared by theprocedure shown. These types of compounds are obtained by the couplingof sunfonamide 33.13 using isocyanate 33.28 bearing R⁴⁴ with a suitablyprotected amine substituent. The phosphonate group bearing moiety isattached by reductive amination using a suitable phosphonate reagent33.30 bearing aldehyde group with reducing agent, such as sodiumcyanoborohydride, in suitable solvents, such as dichloroethane ormethanol, in the presence of an acid, such as acetic acid. The resultingsecondary amine 33.5 (R⁹⁹═H) may be converted to the correspondingtertiary amine 33.5 (R⁹⁹=alkyl) by reductive amination.

For example, a solution of 33.31 in THF is treated with oxalyl chloridefollowed by sodium azide and the resulting acyl azide is converted tothe isocyanate 33.32 by heating. A solution of the sulfonamide 33.18,which is obtained as described in U.S. Pat. No. 3,669,966, in DMF istreated with one equivalent of sodium hydride followed by the isocyanate33.32 to generate 33.33. The Boc protecting group is removed bytreatment with trifluoroacetic acid and the resulting amine is treatedwith one equivalent of 2-oxoethylphosphonate diethyl ester 33.34 withsodium cyanoborohydride and acetic acid in dichloroethane to obtain33.35 in which the linkage is an ethylene group and R⁹⁹ is hydrogen. Theresulting secondary amine 33.35 (R⁹⁹═H) is converted to thecorresponding tertiary amine 33.35 (R⁹⁹=Me) by reductive amination withformaldehyde using sodium cyanoborohydride and acetic acid. Using theabove procedure but employing different sulfonylamide 33.13, isocyanate33.28, and phosphonate reagents 33.30 the corresponding products, whereZ is NH or NR⁹⁹, bearing different R³³, R⁴⁴, R⁹⁹, and linking groups canbe obtained.

Phosphonate analogs of type 33.6 are synthesized according to theprocedure shown. This type of compounds are obtained by the coupling, asdescribed in U.S. Pat. No. 3,669,966, of substituted pyrazine carboxylicacid 33.36 bearing amino, hydroxyl, or other substituents, which canconvert to appropriate functional group for the attachment ofphosphonate moiety, for example carboxylic ester, with sulfonylureamoiety 33.37. Substituted pyrazine carboxylic acids are commerciallyavailable or may be prepared by the method described in Ber. 1907, 40,4850 or in Ber. 1966, 99, 364. Phosphonate moiety is introduced to asubstituent on the pyrazine ring, if necessary after conversion of thesubstituent to a suitable functional group bearing substituent, eitherby alkylation, reductive amination, or reaction with active carbonateintermediate as described previously.

For example, pyrazine-2,5-dicarboxylic acid mono ester 33.39, which isgenerated by partial hydrolysis, is treated with sulfonylurea 33.40 inthe presence of EDC and HOBt to form the amide 33.41. The carboxylicester of 33.41 is then reduced with LiBH₄ in methanol and the resultingalcohol was treated with phenyl chloroformate to generate the activecarbonate. Treatment of the active carbonate with 2-aminoethylphosphonate diethyl ester 33.26 generates the phosphonate analog 33.42in which the linker is carbamate group. The ester may be treated withDIBAL to generate aldehyde functional group and subsequent reductiveamination produces analog 33.43. Using the above procedures butemploying different pyrazine carboxylic acid 33.36, sulfonulurea 33.37,and phosphonate reagents, the corresponding products 33.6 bearingdifferent linking groups can be obtained.

The synthesis of phosphonate analogs of type 33.7 is shown. This type ofcompound is obtained by the coupling, as described in U.S. Pat. No.3,669,966, of substituted benzoic acid 33.44 bearing amino, hydroxyl, orother substituents, which can convert to appropriate functional groupfor the attachment of phosphonate moiety with sulfonylurea moiety 33.37.Phosphonate moiety is introduced to a substituent on the aromatic ring,if necessary after conversion of the substituent to a suitablefunctional group bearing substituent, either by alkylation, reductiveamination, or reaction with active carbonate intermediate as describedpreviously. Alternatively, the phosphorus containing moiety is attachedto a substituent of benzoic acid analogs 33.44 and the resulting 33.45is coupled with sulfonylurea moiety 33.37.

For example, a solution of 3-chloro-2-hydroxybenzoic acid 33.39 in DMFis treated with cesium carbonate and one equivalent of(trifluoromethanesulfonyloxy)methylphosphonic acid diethyl ester to givethe analog 33.12 in which the linkage is a methylene group. Using theabove procedure but employing benzoic acid 33.44, sulfonulurea 33.37,and phosphonate reagents 33.10, 33.22, or 33.30, the correspondingproducts 33.6 bearing different R⁴⁴, R⁶⁶, R⁷⁷, R⁸⁸, and linking groupscan be obtained.

The synthesis of phosphonate analogs of type 33.8 is shown. This type ofcompounds are obtained by the coupling, as described in U.S. Pat. No.4,379,785, of substituted 33.50 bearing amino, hydroxyl, or othersubstituents, which can convert to appropriate functional group for theattachment of phosphorus containing moiety with isocyanate 33.51 bearingsulfonylurea moiety. Alternatively, the phosphorus containing moiety isattached to a substituent of 33.50 and the resulting 33.53 is coupledwith the isocyanate bearing sulfonylurea moiety 33.51. Phosphonatemoiety is introduced to a substituent on 33.50 or 33.53, if necessaryafter conversion of the substituent to a suitable functional groupbearing substituent, either by alkylation, reductive amination, orreaction with active carbonate intermediate as described previously.

For example, 33.54, which is available by the procedure in TetrahedronLett. 2000, 40, 2825, is protected using Boc group and then the silylprotecting group is removed by tetrabutylammonium fluoride, whichresults 33.55. The phosphorus containing moiety is introduced byalkylation using one equivalent of(trifluoromethanesulfonyloxy)methylphosphonic acid diethyl ester 33.11with sodium hydride, and the Boc protecting group is removed usingtrifluoroacetic acid. The reaction of 33.56 with 33.57 in elevatedtemperature produces 33. 58 in which the linkage is a methylene group.Using the above procedure but employing 33.50, 33.51, and phosphonatereagents 33.10, 33.22, or 33.30, the corresponding products 33.6 bearingdifferent heterocycles and linking groups can be obtained.

Example 34

By way of example and not limitation, embodiments of the invention arenamed below in tabular format (Table 100). These embodiments are of thegeneral formula “MBF”:

Each embodiment of MBF is depicted as a substituted nucleus (Sc). Sc isdescribed in formula 1-51 herein, wherein A⁰ is the point of covalentattachment of Sc to Lg, as well as in Tables 1.1 to 1.5 below. For thoseembodiments described in Table 100, Sc is a nucleus designated by anumber and each substituent is designated in order by letter or number.Tables 1.1 to 1.5 are a schedule of nuclei used in forming theembodiments of Table 100. Each nucleus (Sc) is given a numberdesignation from Tables 1.1 to 1.5, and this designation appears firstin each embodiment name. Similarly, Tables 10.1 to 10.19 and 20.1 to20.36 list the selected linking groups (Lg) and prodrug (Pd¹ and Pd²)substituents, again by letter or number designation, respectively.Accordingly, a compound of the formula MBF includes compounds having Scgroups based on formula 1-51 herein as well as compounds according toTable 100 below. In all cases, compounds of the formula MBF have groupsLg, Pd¹ and Pd² setforth in the Tables below.

Accordingly, each named embodiment of Table 100 is depicted by a numberdesignating the nucleus from Table 1.1-1.5, followed by a letterdesignating the linking group (Lg) from Table 10.1-10.19, and twonumbers designating the two prodrug groups (Pd¹ and Pd²) from Table20.1-20.36. In graphical tabular form, each embodiment of Table 100appears as a name having the syntax:

Sc.Lg.Pd¹.Pd²

Each Sc group is shown having a tilda (“˜”). The tilda is the point ofcovalent attachment of Sc to Lg. Q¹ and Q² of the linking groups (Lg),it should be understood, do not represent groups or atoms but are simplyconnectivity designations. Q¹ is the site of the covalent bond to thenucleus (Sc) and Q² is the site of the covalent bond to the phosphorousatom of formula MBF. Each prodrug group (Pd¹ and Pd²) are covalentlybonded to the phosphorous atom of MBF at the tilda symbol (“˜”). Someembodiments of Tables 10.1-10.19 and 20.1-20.36 may be designated as acombination of letters and numbers (Table 10.1-10.19) or number andletter (Table 20.1-20.36). For example there are Table 10 entries forBJ1 and BJ2. In any event, entries of Table 10.1-10.19 always begin witha letter and those of Table 20.1-20.36 always begin with a number. Whena nucleus (Sc) is shown enclosed within square brackets (“[ ]”) and acovalent bond extends outside the brackets, the point of covalentattachment of Sc to Lg may be at any substitutable site on SC. Selectionof the point of attachment is described herein. By way of example andnot limitation, the point of attachment is selected from those depictedin the schemes and examples.

TABLE 1.1

link is 0-8 atoms; 2-6 is preferred

TABLE 1.2

5

6

TABLE 1.3

7

8

9

10

TABLE 1.4

11

12

TABLE 1.5

13

14

TABLE 10.1

A

B

C

D

E

F

G

H

I

J

K

L

M

N

O

TABLE 10.2

P

Q

R

S

T

U

V

W

X

Y

Z

AA

TABLE 10.3

AB

AC

AD

AE

AF

AG

AH

AI

AJ

AK

AL

AM

TABLE 10.4

AN

AO

AP

AQ

AR

AS

AT

AU

AV

AW

AX

AY

TABLE 10.5

AZ

BA

BB

BC

BD

BE

BF

BG

BH

BI

BJ1

BJ2

TABLE 10.6

BK

BL

BM

BN

BO

BP

TABLE 10.7

BQ

BR

BS

BT

BU

BV

TABLE 10.8

BW

BX

BY

BZ

CA

CB

TABLE 10.9

CC

CD

CE

CF

CG

CH

TABLE 10.10

CI

CJ

CK

CL

CM

CN

CO

CP

CQ

CR

CS

CT

TABLE 10.11

CU

CV

CW

CX

CY

CZ

TABLE 10.12

DA

DB

DC

DD

DE

DF

TABLE 10.13

DG

DH

DI

DJ

DK

DL

TABLE 10.14

DM

DN

DO

DP

DQ

DR

TABLE 10.15

DS

DT

DU

DV

DW

DX

DY

DZ

EA

EB

EC

ED

TABLE 10.16

EE

EF

EG

EH

EI

EJ

TABLE 10.17

EK

EL

EM

EN

EO

EP

TABLE 10.18

EQ

ER

ES

ET

EU

EV

TABLE 10.19

EW

EX

EY

EZ

FA

FB

TABLE 20.1

1

2

3

4

5

6

7

8

TABLE 20.2

9

10

11

TABLE 20.3

12

13

14

15

16

17

18

19

TABLE 20.4

20

21

22

TABLE 20.5

23

24

25

26

27

28

29

30

TABLE 20.6

31

32

33

TABLE 20.7

34

35

36

37

38

39

40

41

TABLE 20.8

42

43

44

45

46

47

48

49

TABLE 20.9

50

51

52

53

54

55

56

57

TABLE 20.10

58

59

60

TABLE 20.11

61

62

63

64

65

66

67

68

TABLE 20.12

69

70

71

TABLE 20.13

72

73

74

75

76

77

78

79

TABLE 20.14

80

81

82

TABLE 20.15

83

84

85

86

87

88

89

90

TABLE 20.16

91

92

93

94

95

96

97

98

TABLE 20.17

99

100

101

102

103

104

105

106

TABLE 20.18

107

108

109

TABLE 20.19

110

111

112

113

114

115

116

117

TABLE 20.20

118

119

120

TABLE 20.21

121

122

123

124

125

126

127

128

TABLE 20.22

129

130

131

TABLE 20.23

132 133

134 135

136 137

138 139

TABLE 20.24

140 141

142 143

144 145

146 147

TABLE 20.25

148 149 150

151 152 153

154 155 156

157 158 159

TABLE 20.26

160 161 162

163 164 165

166 167 168

169 170 171

TABLE 20.27

172 173

174 175

176 177

178 179

TABLE 20.28

180

181

182

183

184

185

TABLE 20.29

186 187

188 189

190 191

192 193

TABLE 20.30

194

195

196

197

198

199

TABLE 20.31

200

201

202

203

204

205

207

206

TABLE 20.32

208

209

210

211

212

213

TABLE 20.33

214

215

216

217

218

219

220

221

TABLE 20.34

222

223

224

225

226

227

TABLE 20.35

228 229

230 231

232 233

234 235

TABLE 20.36

236 237

238 239

240 241

242 243

TABLE 20.37

244 245

246 247

TABLE 100 Prodrugs of 1.B 1.B.228.228; 1.B.228.229; 1.B.228.230;1.B.228.231; 1.B.228.236; 1.B.228.237; 1.B.228.238; 1.B.228.239;1.B.228.154; 1.B.228.157; 1.B.228.166; 1.B.228.169; 1.B.228.172;1.B.228.175; 1.B.228.240; 1.B.228.244; 1.B.229.228; 1.B.229.229;1.B.229.230; 1.B.229.231; 1.B.229.236; 1.B.229.237; 1.B.229.238;1.B.229.239; 1.B.229.154; 1.B.229.157; 1.B.229.166; 1.B.229.169;1.B.229.172; 1.B.229.175; 1.B.229.240; 1.B.229.244; 1.B.230.228;1.B.230.229; 1.B.230.230; 1.B.230.231; 1.B.230.236; 1.B.230.237;1.B.230.238; 1.B.230.239; 1.B.230.154; 1.B.230.157; 1.B.230.166;1.B.230.169; 1.B.230.172; 1.B.230.175; 1.B.230.240; 1.B.230.244;1.B.231.228; 1.B.231.229; 1.B.231.230; 1.B.231.231; 1.B.231.236;1.B.231.237; 1.B.231.238; 1.B.231.239; 1.B.231.154; 1.B.231.157;1.B.231.166; 1.B.231.169; 1.B.231.172; 1.B.231.175; 1.B.231.240;1.B.231.244; 1.B.236.228; 1.B.236.229; 1.B.236.230; 1.B.236.231;1.B.236.236; 1.B.236.237; 1.B.236.238; 1.B.236.239; 1.B.236.154;1.B.236.157; 1.B.236.166; 1.B.236.169; 1.B.236.172; 1.B.236.175;1.B.236.240; 1.B.236.244; 1.B.237.228; 1.B.237.229; 1.B.237.230;1.B.237.231; 1.B.237.236; 1.B.237.237; 1.B.237.238; 1.B.237.239;1.B.237.154; 1.B.237.157; 1.B.237.166; 1.B.237.169; 1.B.237.172;1.B.237.175; 1.B.237.240; 1.B.237.244; 1.B.238.228; 1.B.238.229;1.B.238.230; 1.B.238.231; 1.B.238.236; 1.B.238.237; 1.B.238.238;1.B.238.239; 1.B.238.154; 1.B.238.157; 1.B.238.166; 1.B.238.169;1.B.238.172; 1.B.238.175; 1.B.238.240; 1.B.238.244; 1.B.239.228;1.B.239.229; 1.B.239.230; 1.B.239.231; 1.B.239.236; 1.B.239.237;1.B.239.238; 1.B.239.239; 1.B.239.154; 1.B.239.157; 1.B.239.166;1.B.239.169; 1.B.239.172; 1.B.239.175; 1.B.239.240; 1.B.239.244;1.B.154.228; 1.B.154.229; 1.B.154.230; 1.B.154.231; 1.B.154.236;1.B.154.237; 1.B.154.238; 1.B.154.239; 1.B.154.154; 1.B.154.157;1.B.154.166; 1.B.154.169; 1.B.154.172; 1.B.154.175; 1.B.154.240;1.B.154.244; 1.B.157.228; 1.B.157.229; 1.B.157.230; 1.B.157.231;1.B.157.236; 1.B.157.237; 1.B.157.238; 1.B.157.239; 1.B.157.154;1.B.157.157; 1.B.157.166; 1.B.157.169; 1.B.157.172; 1.B.157.175;1.B.157.240; 1.B.157.244; 1.B.166.228; 1.B.166.229; 1.B.166.230;1.B.166.231; 1.B.166.236; 1.B.166.237; 1.B.166.238; 1.B.166.239;1.B.166.154; 1.B.166.157; 1.B.166.166; 1.B.166.169; 1.B.166.172;1.B.166.175; 1.B.166.240; 1.B.166.244; 1.B.169.228; 1.B.169.229;1.B.169.230; 1.B.169.231; 1.B.169.236; 1.B.169.237; 1.B.169.238;1.B.169.239; 1.B.169.154; 1.B.169.157; 1.B.169.166; 1.B.169.169;1.B.169.172; 1.B.169.175; 1.B.169.240; 1.B.169.244; 1.B.172.228;1.B.172.229; 1.B.172.230; 1.B.172.231; 1.B.172.236; 1.B.172.237;1.B.172.238; 1.B.172.239; 1.B.172.154; 1.B.172.157; 1.B.172.166;1.B.172.169; 1.B.172.172; 1.B.172.175; 1.B.172.240; 1.B.172.244;1.B.175.228; 1.B.175.229; 1.B.175.230; 1.B.175.231; 1.B.175.236;1.B.175.237; 1.B.175.238; 1.B.175.239; 1.B.175.154; 1.B.175.157;1.B.175.166; 1.B.175.169; 1.B.175.172; 1.B.175.175; 1.B.175.240;1.B.175.244; 1.B.240.228; 1.B.240.229; 1.B.240.230; 1.B.240.231;1.B.240.236; 1.B.240.237; 1.B.240.238; 1.B.240.239; 1.B.240.154;1.B.240.157; 1.B.240.166; 1.B.240.169; 1.B.240.172; 1.B.240.175;1.B.240.240; 1.B.240.244; 1.B.244.228; 1.B.244.229; 1.B.244.230;1.B.244.231; 1.B.244.236; 1.B.244.237; 1.B.244.238; 1.B.244.239;1.B.244.154; 1.B.244.157; 1.B.244.166; 1.B.244.169; 1.B.244.172;1.B.244.175; 1.B.244.240; 1.B.244.244; Prodrugs of 1.D 1.D.228.228;1.D.228.229; 1.D.228.230; 1.D.228.231; 1.D.228.236; 1.D.228.237;1.D.228.238; 1.D.228.239; 1.D.228.154; 1.D.228.157; 1.D.228.166;1.D.228.169; 1.D.228.172; 1.D.228.175; 1.D.228.240; 1.D.228.244;1.D.229.228; 1.D.229.229; 1.D.229.230; 1.D.229.231; 1.D.229.236;1.D.229.237; 1.D.229.238; 1.D.229.239; 1.D.229.154; 1.D.229.157;1.D.229.166; 1.D.229.169; 1.D.229.172; 1.D.229.175; 1.D.229.240;1.D.229.244; 1.D.230.228; 1.D.230.229; 1.D.230.230; 1.D.230.231;1.D.230.236; 1.D.230.237; 1.D.230.238; 1.D.230.239; 1.D.230.154;1.D.230.157; 1.D.230.166; 1.D.230.169; 1.D.230.172; 1.D.230.175;1.D.230.240; 1.D.230.244; 1.D.231.228; 1.D.231.229; 1.D.231.230;1.D.231.231; 1.D.231.236; 1.D.231.237; 1.D.231.238; 1.D.231.239;1.D.231.154; 1.D.231.157; 1.D.231.166; 1.D.231.169; 1.D.231.172;1.D.231.175; 1.D.231.240; 1.D.231.244; 1.D.236.228; 1.D.236.229;1.D.236.230; 1.D.236.231; 1.D.236.236; 1.D.236.237; 1.D.236.238;1.D.236.239; 1.D.236.154; 1.D.236.157; 1.D.236.166; 1.D.236.169;1.D.236.172; 1.D.236.175; 1.D.236.240; 1.D.236.244; 1.D.237.228;1.D.237.229; 1.D.237.230; 1.D.237.231; 1.D.237.236; 1.D.237.237;1.D.237.238; 1.D.237.239; 1.D.237.154; 1.D.237.157; 1.D.237.166;1.D.237.169; 1.D.237.172; 1.D.237.175; 1.D.237.240; 1.D.237.244;1.D.238.228; 1.D.238.229; 1.D.238.230; 1.D.238.231; 1.D.238.236;1.D.238.237; 1.D.238.238; 1.D.238.239; 1.D.238.154; 1.D.238.157;1.D.238.166; 1.D.238.169; 1.D.238.172; 1.D.238.175; 1.D.238.240;1.D.238.244; 1.D.239.228; 1.D.239.229; 1.D.239.230; 1.D.239.231;1.D.239.236; 1.D.239.237; 1.D.239.238; 1.D.239.239; 1.D.239.154;1.D.239.157; 1.D.239.166; 1.D.239.169; 1.D.239.172; 1.D.239.175;1.D.239.240; 1.D.239.244; 1.D.154.228; 1.D.154.229; 1.D.154.230;1.D.154.231; 1.D.154.236; 1.D.154.237; 1.D.154.238; 1.D.154.239;1.D.154.154; 1.D.154.157; 1.D.154.166; 1.D.154.169; 1.D.154.172;1.D.154.175; 1.D.154.240; 1.D.154.244; 1.D.157.228; 1.D.157.229;1.D.157.230; 1.D.157.231; 1.D.157.236; 1.D.157.237; 1.D.157.238;1.D.157.239; 1.D.157.154; 1.D.157.157; 1.D.157.166; 1.D.157.169;1.D.157.172; 1.D.157.175; 1.D.157.240; 1.D.157.244; 1.D.166.228;1.D.166.229; 1.D.166.230; 1.D.166.231; 1.D.166.236; 1.D.166.237;1.D.166.238; 1.D.166.239; 1.D.166.154; 1.D.166.157; 1.D.166.166;1.D.166.169; 1.D.166.172; 1.D.166.175; 1.D.166.240; 1.D.166.244;1.D.169.228; 1.D.169.229; 1.D.169.230; 1.D.169.231; 1.D.169.236;1.D.169.237; 1.D.169.238; 1.D.169.239; 1.D.169.154; 1.D.169.157;1.D.169.166; 1.D.169.169; 1.D.169.172; 1.D.169.175; 1.D.169.240;1.D.169.244; 1.D.172.228; 1.D.172.229; 1.D.172.230; 1.D.172.231;1.D.172.236; 1.D.172.237; 1.D.172.238; 1.D.172.239; 1.D.172.154;1.D.172.157; 1.D.172.166; 1.D.172.169; 1.D.172.172; 1.D.172.175;1.D.172.240; 1.D.172.244; 1.D.175.228; 1.D.175.229; 1.D.175.230;1.D.175.231; 1.D.175.236; 1.D.175.237; 1.D.175.238; 1.D.175.239;1.D.175.154; 1.D.175.157; 1.D.175.166; 1.D.175.169; 1.D.175.172;1.D.175.175; 1.D.175.240; 1.D.175.244; 1.D.240.228; 1.D.240.229;1.D.240.230; 1.D.240.231; 1.D.240.236; 1.D.240.237; 1.D.240.238;1.D.240.239; 1.D.240.154; 1.D.240.157; 1.D.240.166; 1.D.240.169;1.D.240.172; 1.D.240.175; 1.D.240.240; 1.D.240.244; 1.D.244.228;1.D.244.229; 1.D.244.230; 1.D.244.231; 1.D.244.236; 1.D.244.237;1.D.244.238; 1.D.244.239; 1.D.244.154; 1.D.244.157; 1.D.244.166;1.D.244.169; 1.D.244.172; 1.D.244.175; 1.D.244.240; 1.D.244.244;Prodrugs of 1.E 1.E.228.228; 1.E.228.229; 1.E.228.230; 1.E.228.231;1.E.228.236; 1.E.228.237; 1.E.228.238; 1.E.228.239; 1.E.228.154;1.E.228.157; 1.E.228.166; 1.E.228.169; 1.E.228.172; 1.E.228.175;1.E.228.240; 1.E.228.244; 1.E.229.228; 1.E.229.229; 1.E.229.230;1.E.229.231; 1.E.229.236; 1.E.229.237; 1.E.229.238; 1.E.229.239;1.E.229.154; 1.E.229.157; 1.E.229.166; 1.E.229.169; 1.E.229.172;1.E.229.175; 1.E.229.240; 1.E.229.244; 1.E.230.228; 1.E.230.229;1.E.230.230; 1.E.230.231; 1.E.230.236; 1.E.230.237; 1.E.230.238;1.E.230.239; 1.E.230.154; 1.E.230.157; 1.E.230.166; 1.E.230.169;1.E.230.172; 1.E.230.175; 1.E.230.240; 1.E.230.244; 1.E.231.228;1.E.231.229; 1.E.231.230; 1.E.231.231; 1.E.231.236; 1.E.231.237;1.E.231.238; 1.E.231.239; 1.E.231.154; 1.E.231.157; 1.E.231.166;1.E.231.169; 1.E.231.172; 1.E.231.175; 1.E.231.240; 1.E.231.244;1.E.236.228; 1.E.236.229; 1.E.236.230; 1.E.236.231; 1.E.236.236;1.E.236.237; 1.E.236.238; 1.E.236.239; 1.E.236.154; 1.E.236.157;1.E.236.166; 1.E.236.169; 1.E.236.172; 1.E.236.175; 1.E.236.240;1.E.236.244; 1.E.237.228; 1.E.237.229; 1.E.237.230; 1.E.237.231;1.E.237.236; 1.E.237.237; 1.E.237.238; 1.E.237.239; 1.E.237.154;1.E.237.157; 1.E.237.166; 1.E.237.169; 1.E.237.172; 1.E.237.175;1.E.237.240; 1.E.237.244; 1.E.238.228; 1.E.238.229; 1.E.238.230;1.E.238.231; 1.E.238.236; 1.E.238.237; 1.E.238.238; 1.E.238.239;1.E.238.154; 1.E.238.157; 1.E.238.166; 1.E.238.169; 1.E.238.172;1.E.238.175; 1.E.238.240; 1.E.238.244; 1.E.239.228; 1.E.239.229;1.E.239.230; 1.E.239.231; 1.E.239.236; 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1.E.172.236; 1.E.172.237; 1.E.172.238;1.E.172.239; 1.E.172.154; 1.E.172.157; 1.E.172.166; 1.E.172.169;1.E.172.172; 1.E.172.175; 1.E.172.240; 1.E.172.244; 1.E.175.228;1.E.175.229; 1.E.175.230; 1.E.175.231; 1.E.175.236; 1.E.175.237;1.E.175.238; 1.E.175.239; 1.E.175.154; 1.E.175.157; 1.E.175.166;1.E.175.169; 1.E.175.172; 1.E.175.175; 1.E.175.240; 1.E.175.244;1.E.240.228; 1.E.240.229; 1.E.240.230; 1.E.240.231; 1.E.240.236;1.E.240.237; 1.E.240.238; 1.E.240.239; 1.E.240.154; 1.E.240.157;1.E.240.166; 1.E.240.169; 1.E.240.172; 1.E.240.175; 1.E.240.240;1.E.240.244; 1.E.244.228; 1.E.244.229; 1.E.244.230; 1.E.244.231;1.E.244.236; 1.E.244.237; 1.E.244.238; 1.E.244.239; 1.E.244.154;1.E.244.157; 1.E.244.166; 1.E.244.169; 1.E.244.172; 1.E.244.175;1.E.244.240; 3.D1.E.244.244; Prodrugs of 1.G 1.G.228.228; 1.G.228.229;1.G.228.230; 1.G.228.231; 1.G.228.236; 1.G.228.237; 1.G.228.238;1.G.228.239; 1.G.228.154; 1.G.228.157; 1.G.228.166; 1.G.228.169;1.G.228.172; 1.G.228.175; 1.G.228.240; 1.G.228.244; 1.G.229.228;1.G.229.229; 1.G.229.230; 1.G.229.231; 1.G.229.236; 1.G.229.237;1.G.229.238; 1.G.229.239; 1.G.229.154; 1.G.229.157; 1.G.229.166;1.G.229.169; 1.G.229.172; 1.G.229.175; 1.G.229.240; 1.G.229.244;1.G.230.228; 1.G.230.229; 1.G.230.230; 1.G.230.231; 1.G.230.236;1.G.230.237; 1.G.230.238; 1.G.230.239; 1.G.230.154; 1.G.230.157;1.G.230.166; 1.G.230.169; 1.G.230.172; 1.G.230.175; 1.G.230.240;1.G.230.244; 1.G.231.228; 1.G.231.229; 1.G.231.230; 1.G.231.231;1.G.231.236; 1.G.231.237; 1.G.231.238; 1.G.231.239; 1.G.231.154;1.G.231.157; 1.G.231.166; 1.G.231.169; 1.G.231.172; 1.G.231.175;1.G.231.240; 1.G.231.244; 1.G.236.228; 1.G.236.229; 1.G.236.230;1.G.236.231; 1.G.236.236; 1.G.236.237; 1.G.236.238; 1.G.236.239;1.G.236.154; 1.G.236.157; 1.G.236.166; 1.G.236.169; 1.G.236.172;1.G.236.175; 1.G.236.240; 1.G.236.244; 1.G.237.228; 1.G.237.229;1.G.237.230; 1.G.237.231; 1.G.237.236; 1.G.237.237; 1.G.237.238;1.G.237.239; 1.G.237.154; 1.G.237.157; 1.G.237.166; 1.G.237.169;1.G.237.172; 1.G.237.175; 1.G.237.240; 1.G.237.244; 1.G.238.228;1.G.238.229; 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1.G.169.230; 1.G.169.231; 1.G.169.236; 1.G.169.237;1.G.169.238; 1.G.169.239; 1.G.169.154; 1.G.169.157; 1.G.169.166;1.G.169.169; 1.G.169.172; 1.G.169.175; 1.G.169.240; 1.G.169.244;1.G.172.228; 1.G.172.229; 1.G.172.230; 1.G.172.231; 1.G.172.236;1.G.172.237; 1.G.172.238; 1.G.172.239; 1.G.172.154; 1.G.172.157;1.G.172.166; 1.G.172.169; 1.G.172.172; 1.G.172.175; 1.G.172.240;1.G.172.244; 1.G.175.228; 1.G.175.229; 1.G.175.230; 1.G.175.231;1.G.175.236; 1.G.175.237; 1.G.175.238; 1.G.175.239; 1.G.175.154;1.G.175.157; 1.G.175.166; 1.G.175.169; 1.G.175.172; 1.G.175.175;1.G.175.240; 1.G.175.244; 1.G.240.228; 1.G.240.229; 1.G.240.230;1.G.240.231; 1.G.240.236; 1.G.240.237; 1.G.240.238; 1.G.240.239;1.G.240.154; 1.G.240.157; 1.G.240.166; 1.G.240.169; 1.G.240.172;1.G.240.175; 1.G.240.240; 1.G.240.244; 1.G.244.228; 1.G.244.229;1.G.244.230; 1.G.244.231; 1.G.244.236; 1.G.244.237; 1.G.244.238;1.G.244.239; 1.G.244.154; 1.G.244.157; 1.G.244.166; 1.G.244.169;1.G.244.172; 1.G.244.175; 1.G.244.240; 1.G.244.244; Prodrugs of 1.I1.I.228.228; 1.I.228.229; 1.I.228.230; 1.I.228.231; 1.I.228.236;1.I.228.237; 1.I.228.238; 1.I.228.239; 1.I.228.154; 1.I.228.157;1.I.228.166; 1.I.228.169; 1.I.228.172; 1.I.228.175; 1.I.228.240;1.I.228.244; 1.I.229.228; 1.I.229.229; 1.I.229.230; 1.I.229.231;1.I.229.236; 1.I.229.237; 1.I.229.238; 1.I.229.239; 1.I.229.154;1.I.229.157; 1.I.229.166; 1.I.229.169; 1.I.229.172; 1.I.229.175;1.I.229.240; 1.I.229.244; 1.I.230.228; 1.I.230.229; 1.I.230.230;1.I.230.231; 1.I.230.236; 1.I.230.237; 1.I.230.238; 1.I.230.239;1.I.230.154; 1.I.230.157; 1.I.230.166; 1.I.230.169; 1.I.230.172;1.I.230.175; 1.I.230.240; 1.I.230.244; 1.I.231.228; 1.I.231.229;1.I.231.230; 1.I.231.231; 1.I.231.236; 1.I.231.237; 1.I.231.238;1.I.231.239; 1.I.231.154; 1.I.231.157; 1.I.231.166; 1.I.231.169;1.I.231.172; 1.I.231.175; 1.I.231.240; 1.I.231.244; 1.I.236.228;1.I.236.229; 1.I.236.230; 1.I.236.231; 1.I.236.236; 1.I.236.237;1.I.236.238; 1.I.236.239; 1.I.236.154; 1.I.236.157; 1.I.236.166;1.I.236.169; 1.I.236.172; 1.I.236.175; 1.I.236.240; 1.I.236.244;1.I.237.228; 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1.I.166.229; 1.I.166.230; 1.I.166.231; 1.I.166.236;1.I.166.237; 1.I.166.238; 1.I.166.239; 1.I.166.154; 1.I.166.157;1.I.166.166; 1.I.166.169; 1.I.166.172; 1.I.166.175; 1.I.166.240;1.I.166.244; 1.I.169.228; 1.I.169.229; 1.I.169.230; 1.I.169.231;1.I.169.236; 1.I.169.237; 1.I.169.238; 1.I.169.239; 1.I.169.154;1.I.169.157; 1.I.169.166; 1.I.169.169; 1.I.169.172; 1.I.169.175;1.I.169.240; 1.I.169.244; 1.I.172.228; 1.I.172.229; 1.I.172.230;1.I.172.231; 1.I.172.236; 1.I.172.237; 1.I.172.238; 1.I.172.239;1.I.172.154; 1.I.172.157; 1.I.172.166; 1.I.172.169; 1.I.172.172;1.I.172.175; 1.I.172.240; 1.I.172.244; 1.I.175.228; 1.I.175.229;1.I.175.230; 1.I.175.231; 1.I.175.236; 1.I.175.237; 1.I.175.238;1.I.175.239; 1.I.175.154; 1.I.175.157; 1.I.175.166; 1.I.175.169;1.I.175.172; 1.I.175.175; 1.I.175.240; 1.I.175.244; 1.I.240.228;1.I.240.229; 1.I.240.230; 1.I.240.231; 1.I.240.236; 1.I.240.237;1.I.240.238; 1.I.240.239; 1.I.240.154; 1.I.240.157; 1.I.240.166;1.I.240.169; 1.I.240.172; 1.I.240.175; 1.I.240.240; 1.I.240.244;1.I.244.228; 1.I.244.229; 1.I.244.230; 1.I.244.231; 1.I.244.236;1.I.244.237; 1.I.244.238; 1.I.244.239; 1.I.244.154; 1.I.244.157;1.I.244.166; 1.I.244.169; 1.I.244.172; 1.I.244.175; 1.I.244.240;1.I.244.244; Prodrugs of 1.J 1.J.228.228; 1.J.228.229; 1.J.228.230;1.J.228.231; 1.J.228.236; 1.J.228.237; 1.J.228.238; 1.J.228.239;1.J.228.154; 1.J.228.157; 1.J.228.166; 1.J.228.169; 1.J.228.172;1.J.228.175; 1.J.228.240; 1.J.228.244; 1.J.229.228; 1.J.229.229;1.J.229.230; 1.J.229.231; 1.J.229.236; 1.J.229.237; 1.J.229.238;1.J.229.239; 1.J.229.154; 1.J.229.157; 1.J.229.166; 1.J.229.169;1.J.229.172; 1.J.229.175; 1.J.229.240; 1.J.229.244; 1.J.230.228;1.J.230.229; 1.J.230.230; 1.J.230.231; 1.J.230.236; 1.J.230.237;1.J.230.238; 1.J.230.239; 1.J.230.154; 1.J.230.157; 1.J.230.166;1.J.230.169; 1.J.230.172; 1.J.230.175; 1.J.230.240; 1.J.230.244;1.J.231.228; 1.J.231.229; 1.J.231.230; 1.J.231.231; 1.J.231.236;1.J.231.237; 1.J.231.238; 1.J.231.239; 1.J.231.154; 1.J.231.157;1.J.231.166; 1.J.231.169; 1.J.231.172; 1.J.231.175; 1.J.231.240;1.J.231.244; 1.J.236.228; 1.J.236.229; 1.J.236.230; 1.J.236.231;1.J.236.236; 1.J.236.237; 1.J.236.238; 1.J.236.239; 1.J.236.154;1.J.236.157; 1.J.236.166; 1.J.236.169; 1.J.236.172; 1.J.236.175;1.J.236.240; 1.J.236.244; 1.J.237.228; 1.J.237.229; 1.J.237.230;1.J.237.231; 1.J.237.236; 1.J.237.237; 1.J.237.238; 1.J.237.239;1.J.237.154; 1.J.237.157; 1.J.237.166; 1.J.237.169; 1.J.237.172;1.J.237.175; 1.J.237.240; 1.J.237.244; 1.J.238.228; 1.J.238.229;1.J.238.230; 1.J.238.231; 1.J.238.236; 1.J.238.237; 1.J.238.238;1.J.238.239; 1.J.238.154; 1.J.238.157; 1.J.238.166; 1.J.238.169;1.J.238.172; 1.J.238.175; 1.J.238.240; 1.J.238.244; 1.J.239.228;1.J.239.229; 1.J.239.230; 1.J.239.231; 1.J.239.236; 1.J.239.237;1.J.239.238; 1.J.239.239; 1.J.239.154; 1.J.239.157; 1.J.239.166;1.J.239.169; 1.J.239.172; 1.J.239.175; 1.J.239.240; 1.J.239.244;1.J.154.228; 1.J.154.229; 1.J.154.230; 1.J.154.231; 1.J.154.236;1.J.154.237; 1.J.154.238; 1.J.154.239; 1.J.154.154; 1.J.154.157;1.J.154.166; 1.J.154.169; 1.J.154.172; 1.J.154.175; 1.J.154.240;1.J.154.244; 1.J.157.228; 1.J.157.229; 1.J.157.230; 1.J.157.231;1.J.157.236; 1.J.157.237; 1.J.157.238; 1.J.157.239; 1.J.157.154;1.J.157.157; 1.J.157.166; 1.J.157.169; 1.J.157.172; 1.J.157.175;1.J.157.240; 1.J.157.244; 1.J.166.228; 1.J.166.229; 1.J.166.230;1.J.166.231; 1.J.166.236; 1.J.166.237; 1.J.166.238; 1.J.166.239;1.J.166.154; 1.J.166.157; 1.J.166.166; 1.J.166.169; 1.J.166.172;1.J.166.175; 1.J.166.240; 1.J.166.244; 1.J.169.228; 1.J.169.229;1.J.169.230; 1.J.169.231; 1.J.169.236; 1.J.169.237; 1.J.169.238;1.J.169.239; 1.J.169.154; 1.J.169.157; 1.J.169.166; 1.J.169.169;1.J.169.172; 1.J.169.175; 1.J.169.240; 1.J.169.244; 1.J.172.228;1.J.172.229; 1.J.172.230; 1.J.172.231; 1.J.172.236; 1.J.172.237;1.J.172.238; 1.J.172.239; 1.J.172.154; 1.J.172.157; 1.J.172.166;1.J.172.169; 1.J.172.172; 1.J.172.175; 1.J.172.240; 1.J.172.244;1.J.175.228; 1.J.175.229; 1.J.175.230; 1.J.175.231; 1.J.175.236;1.J.175.237; 1.J.175.238; 1.J.175.239; 1.J.175.154; 1.J.175.157;1.J.175.166; 1.J.175.169; 1.J.175.172; 1.J.175.175; 1.J.175.240;1.J.175.244; 1.J.240.228; 1.J.240.229; 1.J.240.230; 1.J.240.231;1.J.240.236; 1.J.240.237; 1.J.240.238; 1.J.240.239; 1.J.240.154;1.J.240.157; 1.J.240.166; 1.J.240.169; 1.J.240.172; 1.J.240.175;1.J.240.240; 1.J.240.244; 1.J.244.228; 1.J.244.229; 1.J.244.230;1.J.244.231; 1.J.244.236; 1.J.244.237; 1.J.244.238; 1.J.244.239;1.J.244.154; 1.J.244.157; 1.J.244.166; 1.J.244.169; 1.J.244.172;1.J.244.175; 1.J.244.240; 1.J.244.244; Prodrugs of 1.L 1.L.228.228;1.L.228.229; 1.L.228.230; 1.L.228.231; 1.L.228.236; 1.L.228.237;1.L.228.238; 1.L.228.239; 1.L.228.154; 1.L.228.157; 1.L.228.166;1.L.228.169; 1.L.228.172; 1.L.228.175; 1.L.228.240; 1.L.228.244;1.L.229.228; 1.L.229.229; 1.L.229.230; 1.L.229.231; 1.L.229.236;1.L.229.237; 1.L.229.238; 1.L.229.239; 1.L.229.154; 1.L.229.157;1.L.229.166; 1.L.229.169; 1.L.229.172; 1.L.229.175; 1.L.229.240;1.L.229.244; 1.L.230.228; 1.L.230.229; 1.L.230.230; 1.L.230.231;1.L.230.236; 1.L.230.237; 1.L.230.238; 1.L.230.239; 1.L.230.154;1.L.230.157; 1.L.230.166; 1.L.230.169; 1.L.230.172; 1.L.230.175;1.L.230.240; 1.L.230.244; 1.L.231.228; 1.L.231.229; 1.L.231.230;1.L.231.231; 1.L.231.236; 1.L.231.237; 1.L.231.238; 1.L.231.239;1.L.231.154; 1.L.231.157; 1.L.231.166; 1.L.231.169; 1.L.231.172;1.L.231.175; 1.L.231.240; 1.L.231.244; 1.L.236.228; 1.L.236.229;1.L.236.230; 1.L.236.231; 1.L.236.236; 1.L.236.237; 1.L.236.238;1.L.236.239; 1.L.236.154; 1.L.236.157; 1.L.236.166; 1.L.236.169;1.L.236.172; 1.L.236.175; 1.L.236.240; 1.L.236.244; 1.L.237.228;1.L.237.229; 1.L.237.230; 1.L.237.231; 1.L.237.236; 1.L.237.237;1.L.237.238; 1.L.237.239; 1.L.237.154; 1.L.237.157; 1.L.237.166;1.L.237.169; 1.L.237.172; 1.L.237.175; 1.L.237.240; 1.L.237.244;1.L.238.228; 1.L.238.229; 1.L.238.230; 1.L.238.231; 1.L.238.236;1.L.238.237; 1.L.238.238; 1.L.238.239; 1.L.238.154; 1.L.238.157;1.L.238.166; 1.L.238.169; 1.L.238.172; 1.L.238.175; 1.L.238.240;1.L.238.244; 1.L.239.228; 1.L.239.229; 1.L.239.230; 1.L.239.231;1.L.239.236; 1.L.239.237; 1.L.239.238; 1.L.239.239; 1.L.239.154;1.L.239.157; 1.L.239.166; 1.L.239.169; 1.L.239.172; 1.L.239.175;1.L.239.240; 1.L.239.244; 1.L.154.228; 1.L.154.229; 1.L.154.230;1.L.154.231; 1.L.154.236; 1.L.154.237; 1.L.154.238; 1.L.154.239;1.L.154.154; 1.L.154.157; 1.L.154.166; 1.L.154.169; 1.L.154.172;1.L.154.175; 1.L.154.240; 1.L.154.244; 1.L.157.228; 1.L.157.229;1.L.157.230; 1.L.157.231; 1.L.157.236; 1.L.157.237; 1.L.157.238;1.L.157.239; 1.L.157.154; 1.L.157.157; 1.L.157.166; 1.L.157.169;1.L.157.172; 1.L.157.175; 1.L.157.240; 1.L.157.244; 1.L.166.228;1.L.166.229; 1.L.166.230; 1.L.166.231; 1.L.166.236; 1.L.166.237;1.L.166.238; 1.L.166.239; 1.L.166.154; 1.L.166.157; 1.L.166.166;1.L.166.169; 1.L.166.172; 1.L.166.175; 1.L.166.240; 1.L.166.244;1.L.169.228; 1.L.169.229; 1.L.169.230; 1.L.169.231; 1.L.169.236;1.L.169.237; 1.L.169.238; 1.L.169.239; 1.L.169.154; 1.L.169.157;1.L.169.166; 1.L.169.169; 1.L.169.172; 1.L.169.175; 1.L.169.240;1.L.169.244; 1.L.172.228; 1.L.172.229; 1.L.172.230; 1.L.172.231;1.L.172.236; 1.L.172.237; 1.L.172.238; 1.L.172.239; 1.L.172.154;1.L.172.157; 1.L.172.166; 1.L.172.169; 1.L.172.172; 1.L.172.175;1.L.172.240; 1.L.172.244; 1.L.175.228; 1.L.175.229; 1.L.175.230;1.L.175.231; 1.L.175.236; 1.L.175.237; 1.L.175.238; 1.L.175.239;1.L.175.154; 1.L.175.157; 1.L.175.166; 1.L.175.169; 1.L.175.172;1.L.175.175; 1.L.175.240; 1.L.175.244; 1.L.240.228; 1.L.240.229;1.L.240.230; 1.L.240.231; 1.L.240.236; 1.L.240.237; 1.L.240.238;1.L.240.239; 1.L.240.154; 1.L.240.157; 1.L.240.166; 1.L.240.169;1.L.240.172; 1.L.240.175; 1.L.240.240; 1.L.240.244; 1.L.244.228;1.L.244.229; 1.L.244.230; 1.L.244.231; 1.L.244.236; 1.L.244.237;1.L.244.238; 1.L.244.239; 1.L.244.154; 1.L.244.157; 1.L.244.166;1.L.244.169; 1.L.244.172; 1.L.244.175; 1.L.244.240; 1.L.244.244;Prodrugs of 1.O 1.O.228.228; 1.O.228.229; 1.O.228.230; 1.O.228.231;1.O.228.236; 1.O.228.237; 1.O.228.238; 1.O.228.239; 1.O.228.154;1.O.228.157; 1.O.228.166; 1.O.228.169; 1.O.228.172; 1.O.228.175;1.O.228.240; 1.O.228.244; 1.O.229.228; 1.O.229.229; 1.O.229.230;1.O.229.231; 1.O.229.236; 1.O.229.237; 1.O.229.238; 1.O.229.239;1.O.229.154; 1.O.229.157; 1.O.229.166; 1.O.229.169; 1.O.229.172;1.O.229.175; 1.O.229.240; 1.O.229.244; 1.O.230.228; 1.O.230.229;1.O.230.230; 1.O.230.231; 1.O.230.236; 1.O.230.237; 1.O.230.238;1.O.230.239; 1.O.230.154; 1.O.230.157; 1.O.230.166; 1.O.230.169;1.O.230.172; 1.O.230.175; 1.O.230.240; 1.O.230.244; 1.O.231.228;1.O.231.229; 1.O.231.230; 1.O.231.231; 1.O.231.236; 1.O.231.237;1.O.231.238; 1.O.231.239; 1.O.231.154; 1.O.231.157; 1.O.231.166;1.O.231.169; 1.O.231.172; 1.O.231.175; 1.O.231.240; 1.O.231.244;1.O.236.228; 1.O.236.229; 1.O.236.230; 1.O.236.231; 1.O.236.236;1.O.236.237; 1.O.236.238; 1.O.236.239; 1.O.236.154; 1.O.236.157;1.O.236.166; 1.O.236.169; 1.O.236.172; 1.O.236.175; 1.O.236.240;1.O.236.244; 1.O.237.228; 1.O.237.229; 1.O.237.230; 1.O.237.231;1.O.237.236; 1.O.237.237; 1.O.237.238; 1.O.237.239; 1.O.237.154;1.O.237.157; 1.O.237.166; 1.O.237.169; 1.O.237.172; 1.O.237.175;1.O.237.240; 1.O.237.244; 1.O.238.228; 1.O.238.229; 1.O.238.230;1.O.238.231; 1.O.238.236; 1.O.238.237; 1.O.238.238; 1.O.238.239;1.O.238.154; 1.O.238.157; 1.O.238.166; 1.O.238.169; 1.O.238.172;1.O.238.175; 1.O.238.240; 1.O.238.244; 1.O.239.228; 1.O.239.229;1.O.239.230; 1.O.239.231; 1.O.239.236; 1.O.239.237; 1.O.239.238;1.O.239.239; 1.O.239.154; 1.O.239.157; 1.O.239.166; 1.O.239.169;1.O.239.172; 1.O.239.175; 1.O.239.240; 1.O.239.244; 1.O.154.228;1.O.154.229; 1.O.154.230; 1.O.154.231; 1.O.154.236; 1.O.154.237;1.O.154.238; 1.O.154.239; 1.O.154.154; 1.O.154.157; 1.O.154.166;1.O.154.169; 1.O.154.172; 1.O.154.175; 1.O.154.240; 1.O.154.244;1.O.157.228; 1.O.157.229; 1.O.157.230; 1.O.157.231; 1.O.157.236;1.O.157.237; 1.O.157.238; 1.O.157.239; 1.O.157.154; 1.O.157.157;1.O.157.166; 1.O.157.169; 1.O.157.172; 1.O.157.175; 1.O.157.240;1.O.157.244; 1.O.166.228; 1.O.166.229; 1.O.166.230; 1.O.166.231;1.O.166.236; 1.O.166.237; 1.O.166.238; 1.O.166.239; 1.O.166.154;1.O.166.157; 1.O.166.166; 1.O.166.169; 1.O.166.172; 1.O.166.175;1.O.166.240; 1.O.166.244; 1.O.169.228; 1.O.169.229; 1.O.169.230;1.O.169.231; 1.O.169.236; 1.O.169.237; 1.O.169.238; 1.O.169.239;1.O.169.154; 1.O.169.157; 1.O.169.166; 1.O.169.169; 1.O.169.172;1.O.169.175; 1.O.169.240; 1.O.169.244; 1.O.172.228; 1.O.172.229;1.O.172.230; 1.O.172.231; 1.O.172.236; 1.O.172.237; 1.O.172.238;1.O.172.239; 1.O.172.154; 1.O.172.157; 1.O.172.166; 1.O.172.169;1.O.172.172; 1.O.172.175; 1.O.172.240; 1.O.172.244; 1.O.175.228;1.O.175.229; 1.O.175.230; 1.O.175.231; 1.O.175.236; 1.O.175.237;1.O.175.238; 1.O.175.239; 1.O.175.154; 1.O.175.157; 1.O.175.166;1.O.175.169; 1.O.175.172; 1.O.175.175; 1.O.175.240; 1.O.175.244;1.O.240.228; 1.O.240.229; 1.O.240.230; 1.O.240.231; 1.O.240.236;1.O.240.237; 1.O.240.238; 1.O.240.239; 1.O.240.154; 1.O.240.157;1.O.240.166; 1.O.240.169; 1.O.240.172; 1.O.240.175; 1.O.240.240;1.O.240.244; 1.O.244.228; 1.O.244.229; 1.O.244.230; 1.O.244.231;1.O.244.236; 1.O.244.237; 1.O.244.238; 1.O.244.239; 1.O.244.154;1.O.244.157; 1.O.244.166; 1.O.244.169; 1.O.244.172; 1.O.244.175;1.O.244.240; 1.O.244.244; Prodrugs of 1.P 1.P.228.228; 1.P.228.229;1.P.228.230; 1.P.228.231; 1.P.228.236; 1.P.228.237; 1.P.228.238;1.P.228.239; 1.P.228.154; 1.P.228.157; 1.P.228.166; 1.P.228.169;1.P.228.172; 1.P.228.175; 1.P.228.240; 1.P.228.244; 1.P.229.228;1.P.229.229; 1.P.229.230; 1.P.229.231; 1.P.229.236; 1.P.229.237;1.P.229.238; 1.P.229.239; 1.P.229.154; 1.P.229.157; 1.P.229.166;1.P.229.169; 1.P.229.172; 1.P.229.175; 1.P.229.240; 1.P.229.244;1.P.230.228; 1.P.230.229; 1.P.230.230; 1.P.230.231; 1.P.230.236;1.P.230.237; 1.P.230.238; 1.P.230.239; 1.P.230.154; 1.P.230.157;1.P.230.166; 1.P.230.169; 1.P.230.172; 1.P.230.175; 1.P.230.240;1.P.230.244; 1.P.231.228; 1.P.231.229; 1.P.231.230; 1.P.231.231;1.P.231.236; 1.P.231.237; 1.P.231.238; 1.P.231.239; 1.P.231.154;1.P.231.157; 1.P.231.166; 1.P.231.169; 1.P.231.172; 1.P.231.175;1.P.231.240; 1.P.231.244; 1.P.236.228; 1.P.236.229; 1.P.236.230;1.P.236.231; 1.P.236.236; 1.P.236.237; 1.P.236.238; 1.P.236.239;1.P.236.154; 1.P.236.157; 1.P.236.166; 1.P.236.169; 1.P.236.172;1.P.236.175; 1.P.236.240; 1.P.236.244; 1.P.237.228; 1.P.237.229;1.P.237.230; 1.P.237.231; 1.P.237.236; 1.P.237.237; 1.P.237.238;1.P.237.239; 1.P.237.154; 1.P.237.157; 1.P.237.166; 1.P.237.169;1.P.237.172; 1.P.237.175; 1.P.237.240; 1.P.237.244; 1.P.238.228;1.P.238.229; 1.P.238.230; 1.P.238.231; 1.P.238.236; 1.P.238.237;1.P.238.238; 1.P.238.239; 1.P.238.154; 1.P.238.157; 1.P.238.166;1.P.238.169; 1.P.238.172; 1.P.238.175; 1.P.238.240; 1.P.238.244;1.P.239.228; 1.P.239.229; 1.P.239.230; 1.P.239.231; 1.P.239.236;1.P.239.237; 1.P.239.238; 1.P.239.239; 1.P.239.154; 1.P.239.157;1.P.239.166; 1.P.239.169; 1.P.239.172; 1.P.239.175; 1.P.239.240;1.P.239.244; 1.P.154.228; 1.P.154.229; 1.P.154.230; 1.P.154.231;1.P.154.236; 1.P.154.237; 1.P.154.238; 1.P.154.239; 1.P.154.154;1.P.154.157; 1.P.154.166; 1.P.154.169; 1.P.154.172; 1.P.154.175;1.P.154.240; 1.P.154.244; 1.P.157.228; 1.P.157.229; 1.P.157.230;1.P.157.231; 1.P.157.236; 1.P.157.237; 1.P.157.238; 1.P.157.239;1.P.157.154; 1.P.157.157; 1.P.157.166; 1.P.157.169; 1.P.157.172;1.P.157.175; 1.P.157.240; 1.P.157.244; 1.P.166.228; 1.P.166.229;1.P.166.230; 1.P.166.231; 1.P.166.236; 1.P.166.237; 1.P.166.238;1.P.166.239; 1.P.166.154; 1.P.166.157; 1.P.166.166; 1.P.166.169;1.P.166.172; 1.P.166.175; 1.P.166.240; 1.P.166.244; 1.P.169.228;1.P.169.229; 1.P.169.230; 1.P.169.231; 1.P.169.236; 1.P.169.237;1.P.169.238; 1.P.169.239; 1.P.169.154; 1.P.169.157; 1.P.169.166;1.P.169.169; 1.P.169.172; 1.P.169.175; 1.P.169.240; 1.P.169.244;1.P.172.228; 1.P.172.229; 1.P.172.230; 1.P.172.231; 1.P.172.236;1.P.172.237; 1.P.172.238; 1.P.172.239; 1.P.172.154; 1.P.172.157;1.P.172.166; 1.P.172.169; 1.P.172.172; 1.P.172.175; 1.P.172.240;1.P.172.244; 1.P.175.228; 1.P.175.229; 1.P.175.230; 1.P.175.231;1.P.175.236; 1.P.175.237; 1.P.175.238; 1.P.175.239; 1.P.175.154;1.P.175.157; 1.P.175.166; 1.P.175.169; 1.P.175.172; 1.P.175.175;1.P.175.240; 1.P.175.244; 1.P.240.228; 1.P.240.229; 1.P.240.230;1.P.240.231; 1.P.240.236; 1.P.240.237; 1.P.240.238; 1.P.240.239;1.P.240.154; 1.P.240.157; 1.P.240.166; 1.P.240.169; 1.P.240.172;1.P.240.175; 1.P.240.240; 1.P.240.244; 1.P.244.228; 1.P.244.229;1.P.244.230; 1.P.244.231; 1.P.244.236; 1.P.244.237; 1.P.244.238;1.P.244.239; 1.P.244.154; 1.P.244.157; 1.P.244.166; 1.P.244.169;1.P.244.172; 1.P.244.175; 1.P.244.240; 1.P.244.244; Prodrugs of 1.U1.U.228.228; 1.U.228.229; 1.U.228.230; 1.U.228.231; 1.U.228.236;1.U.228.237; 1.U.228.238; 1.U.228.239; 1.U.228.154; 1.U.228.157;1.U.228.166; 1.U.228.169; 1.U.228.172; 1.U.228.175; 1.U.228.240;1.U.228.244; 1.U.229.228; 1.U.229.229; 1.U.229.230; 1.U.229.231;1.U.229.236; 1.U.229.237; 1.U.229.238; 1.U.229.239; 1.U.229.154;1.U.229.157; 1.U.229.166; 1.U.229.169; 1.U.229.172; 1.U.229.175;1.U.229.240; 1.U.229.244; 1.U.230.228; 1.U.230.229; 1.U.230.230;1.U.230.231; 1.U.230.236; 1.U.230.237; 1.U.230.238; 1.U.230.239;1.U.230.154; 1.U.230.157; 1.U.230.166; 1.U.230.169; 1.U.230.172;1.U.230.175; 1.U.230.240; 1.U.230.244; 1.U.231.228; 1.U.231.229;1.U.231.230; 1.U.231.231; 1.U.231.236; 1.U.231.237; 1.U.231.238;1.U.231.239; 1.U.231.154; 1.U.231.157; 1.U.231.166; 1.U.231.169;1.U.231.172; 1.U.231.175; 1.U.231.240; 1.U.231.244; 1.U.236.228;1.U.236.229; 1.U.236.230; 1.U.236.231; 1.U.236.236; 1.U.236.237;1.U.236.238; 1.U.236.239; 1.U.236.154; 1.U.236.157; 1.U.236.166;1.U.236.169; 1.U.236.172; 1.U.236.175; 1.U.236.240; 1.U.236.244;1.U.237.228; 1.U.237.229; 1.U.237.230; 1.U.237.231; 1.U.237.236;1.U.237.237; 1.U.237.238; 1.U.237.239; 1.U.237.154; 1.U.237.157;1.U.237.166; 1.U.237.169; 1.U.237.172; 1.U.237.175; 1.U.237.240;1.U.237.244; 1.U.238.228; 1.U.238.229; 1.U.238.230; 1.U.238.231;1.U.238.236; 1.U.238.237; 1.U.238.238; 1.U.238.239; 1.U.238.154;1.U.238.157; 1.U.238.166; 1.U.238.169; 1.U.238.172; 1.U.238.175;1.U.238.240; 1.U.238.244; 1.U.239.228; 1.U.239.229; 1.U.239.230;1.U.239.231; 1.U.239.236; 1.U.239.237; 1.U.239.238; 1.U.239.239;1.U.239.154; 1.U.239.157; 1.U.239.166; 1.U.239.169; 1.U.239.172;1.U.239.175; 1.U.239.240; 1.U.239.244; 1.U.154.228; 1.U.154.229;1.U.154.230; 1.U.154.231; 1.U.154.236; 1.U.154.237; 1.U.154.238;1.U.154.239; 1.U.154.154; 1.U.154.157; 1.U.154.166; 1.U.154.169;1.U.154.172; 1.U.154.175; 1.U.154.240; 1.U.154.244; 1.U.157.228;1.U.157.229; 1.U.157.230; 1.U.157.231; 1.U.157.236; 1.U.157.237;1.U.157.238; 1.U.157.239; 1.U.157.154; 1.U.157.157; 1.U.157.166;1.U.157.169; 1.U.157.172; 1.U.157.175; 1.U.157.240; 1.U.157.244;1.U.166.228; 1.U.166.229; 1.U.166.230; 1.U.166.231; 1.U.166.236;1.U.166.237; 1.U.166.238; 1.U.166.239; 1.U.166.154; 1.U.166.157;1.U.166.166; 1.U.166.169; 1.U.166.172; 1.U.166.175; 1.U.166.240;1.U.166.244; 1.U.169.228; 1.U.169.229; 1.U.169.230; 1.U.169.231;1.U.169.236; 1.U.169.237; 1.U.169.238; 1.U.169.239; 1.U.169.154;1.U.169.157; 1.U.169.166; 1.U.169.169; 1.U.169.172; 1.U.169.175;1.U.169.240; 1.U.169.244; 1.U.172.228; 1.U.172.229; 1.U.172.230;1.U.172.231; 1.U.172.236; 1.U.172.237; 1.U.172.238; 1.U.172.239;1.U.172.154; 1.U.172.157; 1.U.172.166; 1.U.172.169; 1.U.172.172;1.U.172.175; 1.U.172.240; 1.U.172.244; 1.U.175.228; 1.U.175.229;1.U.175.230; 1.U.175.231; 1.U.175.236; 1.U.175.237; 1.U.175.238;1.U.175.239; 1.U.175.154; 1.U.175.157; 1.U.175.166; 1.U.175.169;1.U.175.172; 1.U.175.175; 1.U.175.240; 1.U.175.244; 1.U.240.228;1.U.240.229; 1.U.240.230; 1.U.240.231; 1.U.240.236; 1.U.240.237;1.U.240.238; 1.U.240.239; 1.U.240.154; 1.U.240.157; 1.U.240.166;1.U.240.169; 1.U.240.172; 1.U.240.175; 1.U.240.240; 1.U.240.244;1.U.244.228; 1.U.244.229; 1.U.244.230; 1.U.244.231; 1.U.244.236;1.U.244.237; 1.U.244.238; 1.U.244.239; 1.U.244.154; 1.U.244.157;1.U.244.166; 1.U.244.169; 1.U.244.172; 1.U.244.175; 1.U.244.240;1.U.244.244; Prodrugs of 1.W 1.W.228.228; 1.W.228.229; 1.W.228.230;1.W.228.231; 1.W.228.236; 1.W.228.237; 1.W.228.238; 1.W.228.239;1.W.228.154; 1.W.228.157; 1.W.228.166; 1.W.228.169; 1.W.228.172;1.W.228.175; 1.W.228.240; 1.W.228.244; 1.W.229.228; 1.W.229.229;1.W.229.230; 1.W.229.231; 1.W.229.236; 1.W.229.237; 1.W.229.238;1.W.229.239; 1.W.229.154; 1.W.229.157; 1.W.229.166; 1.W.229.169;1.W.229.172; 1.W.229.175; 1.W.229.240; 1.W.229.244; 1.W.230.228;1.W.230.229; 1.W.230.230; 1.W.230.231; 1.W.230.236; 1.W.230.237;1.W.230.238; 1.W.230.239; 1.W.230.154; 1.W.230.157; 1.W.230.166;1.W.230.169; 1.W.230.172; 1.W.230.175; 1.W.230.240; 1.W.230.244;1.W.231.228; 1.W.231.229; 1.W.231.230; 1.W.231.231; 1.W.231.236;1.W.231.237; 1.W.231.238; 1.W.231.239; 1.W.231.154; 1.W.231.157;1.W.231.166; 1.W.231.169; 1.W.231.172; 1.W.231.175; 1.W.231.240;1.W.231.244; 1.W.236.228; 1.W.236.229; 1.W.236.230; 1.W.236.231;1.W.236.236; 1.W.236.237; 1.W.236.238; 1.W.236.239; 1.W.236.154;1.W.236.157; 1.W.236.166; 1.W.236.169; 1.W.236.172; 1.W.236.175;1.W.236.240; 1.W.236.244; 1.W.237.228; 1.W.237.229; 1.W.237.230;1.W.237.231; 1.W.237.236; 1.W.237.237; 1.W.237.238; 1.W.237.239;1.W.237.154; 1.W.237.157; 1.W.237.166; 1.W.237.169; 1.W.237.172;1.W.237.175; 1.W.237.240; 1.W.237.244; 1.W.238.228; 1.W.238.229;1.W.238.230; 1.W.238.231; 1.W.238.236; 1.W.238.237; 1.W.238.238;1.W.238.239; 1.W.238.154; 1.W.238.157; 1.W.238.166; 1.W.238.169;1.W.238.172; 1.W.238.175; 1.W.238.240; 1.W.238.244; 1.W.239.228;1.W.239.229; 1.W.239.230; 1.W.239.231; 1.W.239.236; 1.W.239.237;1.W.239.238; 1.W.239.239; 1.W.239.154; 1.W.239.157; 1.W.239.166;1.W.239.169; 1.W.239.172; 1.W.239.175; 1.W.239.240; 1.W.239.244;1.W.154.228; 1.W.154.229; 1.W.154.230; 1.W.154.231; 1.W.154.236;1.W.154.237; 1.W.154.238; 1.W.154.239; 1.W.154.154; 1.W.154.157;1.W.154.166; 1.W.154.169; 1.W.154.172; 1.W.154.175; 1.W.154.240;1.W.154.244; 1.W.157.228; 1.W.157.229; 1.W.157.230; 1.W.157.231;1.W.157.236; 1.W.157.237; 1.W.157.238; 1.W.157.239; 1.W.157.154;1.W.157.157; 1.W.157.166; 1.W.157.169; 1.W.157.172; 1.W.157.175;1.W.157.240; 1.W.157.244; 1.W.166.228; 1.W.166.229; 1.W.166.230;1.W.166.231; 1.W.166.236; 1.W.166.237; 1.W.166.238; 1.W.166.239;1.W.166.154; 1.W.166.157; 1.W.166.166; 1.W.166.169; 1.W.166.172;1.W.166.175; 1.W.166.240; 1.W.166.244; 1.W.169.228; 1.W.169.229;1.W.169.230; 1.W.169.231; 1.W.169.236; 1.W.169.237; 1.W.169.238;1.W.169.239; 1.W.169.154; 1.W.169.157; 1.W.169.166; 1.W.169.169;1.W.169.172; 1.W.169.175; 1.W.169.240; 1.W.169.244; 1.W.172.228;1.W.172.229; 1.W.172.230; 1.W.172.231; 1.W.172.236; 1.W.172.237;1.W.172.238; 1.W.172.239; 1.W.172.154; 1.W.172.157; 1.W.172.166;1.W.172.169; 1.W.172.172; 1.W.172.175; 1.W.172.240; 1.W.172.244;1.W.175.228; 1.W.175.229; 1.W.175.230; 1.W.175.231; 1.W.175.236;1.W.175.237; 1.W.175.238; 1.W.175.239; 1.W.175.154; 1.W.175.157;1.W.175.166; 1.W.175.169; 1.W.175.172; 1.W.175.175; 1.W.175.240;1.W.175.244; 1.W.240.228; 1.W.240.229; 1.W.240.230; 1.W.240.231;1.W.240.236; 1.W.240.237; 1.W.240.238; 1.W.240.239; 1.W.240.154;1.W.240.157; 1.W.240.166; 1.W.240.169; 1.W.240.172; 1.W.240.175;1.W.240.240; 1.W.240.244; 1.W.244.228; 1.W.244.229; 1.W.244.230;1.W.244.231; 1.W.244.236; 1.W.244.237; 1.W.244.238; 1.W.244.239;1.W.244.154; 1.W.244.157; 1.W.244.166; 1.W.244.169; 1.W.244.172;1.W.244.175; 1.W.244.240; 1.W.244.244; Prodrugs of 1.Y 1.Y.228.228;1.Y.228.229; 1.Y.228.230; 1.Y.228.231; 1.Y.228.236; 1.Y.228.237;1.Y.228.238; 1.Y.228.239; 1.Y.228.154; 1.Y.228.157; 1.Y.228.166;1.Y.228.169; 1.Y.228.172; 1.Y.228.175; 1.Y.228.240; 1.Y.228.244;1.Y.229.228; 1.Y.229.229; 1.Y.229.230; 1.Y.229.231; 1.Y.229.236;1.Y.229.237; 1.Y.229.238; 1.Y.229.239; 1.Y.229.154; 1.Y.229.157;1.Y.229.166; 1.Y.229.169; 1.Y.229.172; 1.Y.229.175; 1.Y.229.240;1.Y.229.244; 1.Y.230.228; 1.Y.230.229; 1.Y.230.230; 1.Y.230.231;1.Y.230.236; 1.Y.230.237; 1.Y.230.238; 1.Y.230.239; 1.Y.230.154;1.Y.230.157; 1.Y.230.166; 1.Y.230.169; 1.Y.230.172; 1.Y.230.175;1.Y.230.240; 1.Y.230.244; 1.Y.231.228; 1.Y.231.229; 1.Y.231.230;1.Y.231.231; 1.Y.231.236; 1.Y.231.237; 1.Y.231.238; 1.Y.231.239;1.Y.231.154; 1.Y.231.157; 1.Y.231.166; 1.Y.231.169; 1.Y.231.172;1.Y.231.175; 1.Y.231.240; 1.Y.231.244; 1.Y.236.228; 1.Y.236.229;1.Y.236.230; 1.Y.236.231; 1.Y.236.236; 1.Y.236.237; 1.Y.236.238;1.Y.236.239; 1.Y.236.154; 1.Y.236.157; 1.Y.236.166; 1.Y.236.169;1.Y.236.172; 1.Y.236.175; 1.Y.236.240; 1.Y.236.244; 1.Y.237.228;1.Y.237.229; 1.Y.237.230; 1.Y.237.231; 1.Y.237.236; 1.Y.237.237;1.Y.237.238; 1.Y.237.239; 1.Y.237.154; 1.Y.237.157; 1.Y.237.166;1.Y.237.169; 1.Y.237.172; 1.Y.237.175; 1.Y.237.240; 1.Y.237.244;1.Y.238.228; 1.Y.238.229; 1.Y.238.230; 1.Y.238.231; 1.Y.238.236;1.Y.238.237; 1.Y.238.238; 1.Y.238.239; 1.Y.238.154; 1.Y.238.157;1.Y.238.166; 1.Y.238.169; 1.Y.238.172; 1.Y.238.175; 1.Y.238.240;1.Y.238.244; 1.Y.239.228; 1.Y.239.229; 1.Y.239.230; 1.Y.239.231;1.Y.239.236; 1.Y.239.237; 1.Y.239.238; 1.Y.239.239; 1.Y.239.154;1.Y.239.157; 1.Y.239.166; 1.Y.239.169; 1.Y.239.172; 1.Y.239.175;1.Y.239.240; 1.Y.239.244; 1.Y.154.228; 1.Y.154.229; 1.Y.154.230;1.Y.154.231; 1.Y.154.236; 1.Y.154.237; 1.Y.154.238; 1.Y.154.239;1.Y.154.154; 1.Y.154.157; 1.Y.154.166; 1.Y.154.169; 1.Y.154.172;1.Y.154.175; 1.Y.154.240; 1.Y.154.244; 1.Y.157.228; 1.Y.157.229;1.Y.157.230; 1.Y.157.231; 1.Y.157.236; 1.Y.157.237; 1.Y.157.238;1.Y.157.239; 1.Y.157.154; 1.Y.157.157; 1.Y.157.166; 1.Y.157.169;1.Y.157.172; 1.Y.157.175; 1.Y.157.240; 1.Y.157.244; 1.Y.166.228;1.Y.166.229; 1.Y.166.230; 1.Y.166.231; 1.Y.166.236; 1.Y.166.237;1.Y.166.238; 1.Y.166.239; 1.Y.166.154; 1.Y.166.157; 1.Y.166.166;1.Y.166.169; 1.Y.166.172; 1.Y.166.175; 1.Y.166.240; 1.Y.166.244;1.Y.169.228; 1.Y.169.229; 1.Y.169.230; 1.Y.169.231; 1.Y.169.236;1.Y.169.237; 1.Y.169.238; 1.Y.169.239; 1.Y.169.154; 1.Y.169.157;1.Y.169.166; 1.Y.169.169; 1.Y.169.172; 1.Y.169.175; 1.Y.169.240;1.Y.169.244; 1.Y.172.228; 1.Y.172.229; 1.Y.172.230; 1.Y.172.231;1.Y.172.236; 1.Y.172.237; 1.Y.172.238; 1.Y.172.239; 1.Y.172.154;1.Y.172.157; 1.Y.172.166; 1.Y.172.169; 1.Y.172.172; 1.Y.172.175;1.Y.172.240; 1.Y.172.244; 1.Y.175.228; 1.Y.175.229; 1.Y.175.230;1.Y.175.231; 1.Y.175.236; 1.Y.175.237; 1.Y.175.238; 1.Y.175.239;1.Y.175.154; 1.Y.175.157; 1.Y.175.166; 1.Y.175.169; 1.Y.175.172;1.Y.175.175; 1.Y.175.240; 1.Y.175.244; 1.Y.240.228; 1.Y.240.229;1.Y.240.230; 1.Y.240.231; 1.Y.240.236; 1.Y.240.237; 1.Y.240.238;1.Y.240.239; 1.Y.240.154; 1.Y.240.157; 1.Y.240.166; 1.Y.240.169;1.Y.240.172; 1.Y.240.175; 1.Y.240.240; 1.Y.240.244; 1.Y.244.228;1.Y.244.229; 1.Y.244.230; 1.Y.244.231; 1.Y.244.236; 1.Y.244.237;1.Y.244.238; 1.Y.244.239; 1.Y.244.154; 1.Y.244.157; 1.Y.244.166;1.Y.244.169; 1.Y.244.172; 1.Y.244.175; 1.Y.244.240; 1.Y.244.244;Prodrugs of 2.B 2.B.228.228; 2.B.228.229; 2.B.228.230; 2.B.228.231;2.B.228.236; 2.B.228.237; 2.B.228.238; 2.B.228.239; 2.B.228.154;2.B.228.157; 2.B.228.166; 2.B.228.169; 2.B.228.172; 2.B.228.175;2.B.228.240; 2.B.228.244; 2.B.229.228; 2.B.229.229; 2.B.229.230;2.B.229.231; 2.B.229.236; 2.B.229.237; 2.B.229.238; 2.B.229.239;2.B.229.154; 2.B.229.157; 2.B.229.166; 2.B.229.169; 2.B.229.172;2.B.229.175; 2.B.229.240; 2.B.229.244; 2.B.230.228; 2.B.230.229;2.B.230.230; 2.B.230.231; 2.B.230.236; 2.B.230.237; 2.B.230.238;2.B.230.239; 2.B.230.154; 2.B.230.157; 2.B.230.166; 2.B.230.169;2.B.230.172; 2.B.230.175; 2.B.230.240; 2.B.230.244; 2.B.231.228;2.B.231.229; 2.B.231.230; 2.B.231.231; 2.B.231.236; 2.B.231.237;2.B.231.238; 2.B.231.239; 2.B.231.154; 2.B.231.157; 2.B.231.166;2.B.231.169; 2.B.231.172; 2.B.231.175; 2.B.231.240; 2.B.231.244;2.B.236.228; 2.B.236.229; 2.B.236.230; 2.B.236.231; 2.B.236.236;2.B.236.237; 2.B.236.238; 2.B.236.239; 2.B.236.154; 2.B.236.157;2.B.236.166; 2.B.236.169; 2.B.236.172; 2.B.236.175; 2.B.236.240;2.B.236.244; 2.B.237.228; 2.B.237.229; 2.B.237.230; 2.B.237.231;2.B.237.236; 2.B.237.237; 2.B.237.238; 2.B.237.239; 2.B.237.154;2.B.237.157; 2.B.237.166; 2.B.237.169; 2.B.237.172; 2.B.237.175;2.B.237.240; 2.B.237.244; 2.B.238.228; 2.B.238.229; 2.B.238.230;2.B.238.231; 2.B.238.236; 2.B.238.237; 2.B.238.238; 2.B.238.239;2.B.238.154; 2.B.238.157; 2.B.238.166; 2.B.238.169; 2.B.238.172;2.B.238.175; 2.B.238.240; 2.B.238.244; 2.B.239.228; 2.B.239.229;2.B.239.230; 2.B.239.231; 2.B.239.236; 2.B.239.237; 2.B.239.238;2.B.239.239; 2.B.239.154; 2.B.239.157; 2.B.239.166; 2.B.239.169;2.B.239.172; 2.B.239.175; 2.B.239.240; 2.B.239.244; 2.B.154.228;2.B.154.229; 2.B.154.230; 2.B.154.231; 2.B.154.236; 2.B.154.237;2.B.154.238; 2.B.154.239; 2.B.154.154; 2.B.154.157; 2.B.154.166;2.B.154.169; 2.B.154.172; 2.B.154.175; 2.B.154.240; 2.B.154.244;2.B.157.228; 2.B.157.229; 2.B.157.230; 2.B.157.231; 2.B.157.236;2.B.157.237; 2.B.157.238; 2.B.157.239; 2.B.157.154; 2.B.157.157;2.B.157.166; 2.B.157.169; 2.B.157.172; 2.B.157.175; 2.B.157.240;2.B.157.244; 2.B.166.228; 2.B.166.229; 2.B.166.230; 2.B.166.231;2.B.166.236; 2.B.166.237; 2.B.166.238; 2.B.166.239; 2.B.166.154;2.B.166.157; 2.B.166.166; 2.B.166.169; 2.B.166.172; 2.B.166.175;2.B.166.240; 2.B.166.244; 2.B.169.228; 2.B.169.229; 2.B.169.230;2.B.169.231; 2.B.169.236; 2.B.169.237; 2.B.169.238; 2.B.169.239;2.B.169.154; 2.B.169.157; 2.B.169.166; 2.B.169.169; 2.B.169.172;2.B.169.175; 2.B.169.240; 2.B.169.244; 2.B.172.228; 2.B.172.229;2.B.172.230; 2.B.172.231; 2.B.172.236; 2.B.172.237; 2.B.172.238;2.B.172.239; 2.B.172.154; 2.B.172.157; 2.B.172.166; 2.B.172.169;2.B.172.172; 2.B.172.175; 2.B.172.240; 2.B.172.244; 2.B.175.228;2.B.175.229; 2.B.175.230; 2.B.175.231; 2.B.175.236; 2.B.175.237;2.B.175.238; 2.B.175.239; 2.B.175.154; 2.B.175.157; 2.B.175.166;2.B.175.169; 2.B.175.172; 2.B.175.175; 2.B.175.240; 2.B.175.244;2.B.240.228; 2.B.240.229; 2.B.240.230; 2.B.240.231; 2.B.240.236;2.B.240.237; 2.B.240.238; 2.B.240.239; 2.B.240.154; 2.B.240.157;2.B.240.166; 2.B.240.169; 2.B.240.172; 2.B.240.175; 2.B.240.240;2.B.240.244; 2.B.244.228; 2.B.244.229; 2.B.244.230; 2.B.244.231;2.B.244.236; 2.B.244.237; 2.B.244.238; 2.B.244.239; 2.B.244.154;2.B.244.157; 2.B.244.166; 2.B.244.169; 2.B.244.172; 2.B.244.175;2.B.244.240; 2.B.244.244; Prodrugs of 2.D 2.D.228.228; 2.D.228.229;2.D.228.230; 2.D.228.231; 2.D.228.236; 2.D.228.237; 2.D.228.238;2.D.228.239; 2.D.228.154; 2.D.228.157; 2.D.228.166; 2.D.228.169;2.D.228.172; 2.D.228.175; 2.D.228.240; 2.D.228.244; 2.D.229.228;2.D.229.229; 2.D.229.230; 2.D.229.231; 2.D.229.236; 2.D.229.237;2.D.229.238; 2.D.229.239; 2.D.229.154; 2.D.229.157; 2.D.229.166;2.D.229.169; 2.D.229.172; 2.D.229.175; 2.D.229.240; 2.D.229.244;2.D.230.228; 2.D.230.229; 2.D.230.230; 2.D.230.231; 2.D.230.236;2.D.230.237; 2.D.230.238; 2.D.230.239; 2.D.230.154; 2.D.230.157;2.D.230.166; 2.D.230.169; 2.D.230.172; 2.D.230.175; 2.D.230.240;2.D.230.244; 2.D.231.228; 2.D.231.229; 2.D.231.230; 2.D.231.231;2.D.231.236; 2.D.231.237; 2.D.231.238; 2.D.231.239; 2.D.231.154;2.D.231.157; 2.D.231.166; 2.D.231.169; 2.D.231.172; 2.D.231.175;2.D.231.240; 2.D.231.244; 2.D.236.228; 2.D.236.229; 2.D.236.230;2.D.236.231; 2.D.236.236; 2.D.236.237; 2.D.236.238; 2.D.236.239;2.D.236.154; 2.D.236.157; 2.D.236.166; 2.D.236.169; 2.D.236.172;2.D.236.175; 2.D.236.240; 2.D.236.244; 2.D.237.228; 2.D.237.229;2.D.237.230; 2.D.237.231; 2.D.237.236; 2.D.237.237; 2.D.237.238;2.D.237.239; 2.D.237.154; 2.D.237.157; 2.D.237.166; 2.D.237.169;2.D.237.172; 2.D.237.175; 2.D.237.240; 2.D.237.244; 2.D.238.228;2.D.238.229; 2.D.238.230; 2.D.238.231; 2.D.238.236; 2.D.238.237;2.D.238.238; 2.D.238.239; 2.D.238.154; 2.D.238.157; 2.D.238.166;2.D.238.169; 2.D.238.172; 2.D.238.175; 2.D.238.240; 2.D.238.244;2.D.239.228; 2.D.239.229; 2.D.239.230; 2.D.239.231; 2.D.239.236;2.D.239.237; 2.D.239.238; 2.D.239.239; 2.D.239.154; 2.D.239.157;2.D.239.166; 2.D.239.169; 2.D.239.172; 2.D.239.175; 2.D.239.240;2.D.239.244; 2.D.154.228; 2.D.154.229; 2.D.154.230; 2.D.154.231;2.D.154.236; 2.D.154.237; 2.D.154.238; 2.D.154.239; 2.D.154.154;2.D.154.157; 2.D.154.166; 2.D.154.169; 2.D.154.172; 2.D.154.175;2.D.154.240; 2.D.154.244; 2.D.157.228; 2.D.157.229; 2.D.157.230;2.D.157.231; 2.D.157.236; 2.D.157.237; 2.D.157.238; 2.D.157.239;2.D.157.154; 2.D.157.157; 2.D.157.166; 2.D.157.169; 2.D.157.172;2.D.157.175; 2.D.157.240; 2.D.157.244; 2.D.166.228; 2.D.166.229;2.D.166.230; 2.D.166.231; 2.D.166.236; 2.D.166.237; 2.D.166.238;2.D.166.239; 2.D.166.154; 2.D.166.157; 2.D.166.166; 2.D.166.169;2.D.166.172; 2.D.166.175; 2.D.166.240; 2.D.166.244; 2.D.169.228;2.D.169.229; 2.D.169.230; 2.D.169.231; 2.D.169.236; 2.D.169.237;2.D.169.238; 2.D.169.239; 2.D.169.154; 2.D.169.157; 2.D.169.166;2.D.169.169; 2.D.169.172; 2.D.169.175; 2.D.169.240; 2.D.169.244;2.D.172.228; 2.D.172.229; 2.D.172.230; 2.D.172.231; 2.D.172.236;2.D.172.237; 2.D.172.238; 2.D.172.239; 2.D.172.154; 2.D.172.157;2.D.172.166; 2.D.172.169; 2.D.172.172; 2.D.172.175; 2.D.172.240;2.D.172.244; 2.D.175.228; 2.D.175.229; 2.D.175.230; 2.D.175.231;2.D.175.236; 2.D.175.237; 2.D.175.238; 2.D.175.239; 2.D.175.154;2.D.175.157; 2.D.175.166; 2.D.175.169; 2.D.175.172; 2.D.175.175;2.D.175.240; 2.D.175.244; 2.D.240.228; 2.D.240.229; 2.D.240.230;2.D.240.231; 2.D.240.236; 2.D.240.237; 2.D.240.238; 2.D.240.239;2.D.240.154; 2.D.240.157; 2.D.240.166; 2.D.240.169; 2.D.240.172;2.D.240.175; 2.D.240.240; 2.D.240.244; 2.D.244.228; 2.D.244.229;2.D.244.230; 2.D.244.231; 2.D.244.236; 2.D.244.237; 2.D.244.238;2.D.244.239; 2.D.244.154; 2.D.244.157; 2.D.244.166; 2.D.244.169;2.D.244.172; 2.D.244.175; 2.D.244.240; 2.D.244.244; Prodrugs of 2.E2.E.228.228; 2.E.228.229; 2.E.228.230; 2.E.228.231; 2.E.228.236;2.E.228.237; 2.E.228.238; 2.E.228.239; 2.E.228.154; 2.E.228.157;2.E.228.166; 2.E.228.169; 2.E.228.172; 2.E.228.175; 2.E.228.240;2.E.228.244; 2.E.229.228; 2.E.229.229; 2.E.229.230; 2.E.229.231;2.E.229.236; 2.E.229.237; 2.E.229.238; 2.E.229.239; 2.E.229.154;2.E.229.157; 2.E.229.166; 2.E.229.169; 2.E.229.172; 2.E.229.175;2.E.229.240; 2.E.229.244; 2.E.230.228; 2.E.230.229; 2.E.230.230;2.E.230.231; 2.E.230.236; 2.E.230.237; 2.E.230.238; 2.E.230.239;2.E.230.154; 2.E.230.157; 2.E.230.166; 2.E.230.169; 2.E.230.172;2.E.230.175; 2.E.230.240; 2.E.230.244; 2.E.231.228; 2.E.231.229;2.E.231.230; 2.E.231.231; 2.E.231.236; 2.E.231.237; 2.E.231.238;2.E.231.239; 2.E.231.154; 2.E.231.157; 2.E.231.166; 2.E.231.169;2.E.231.172; 2.E.231.175; 2.E.231.240; 2.E.231.244; 2.E.236.228;2.E.236.229; 2.E.236.230; 2.E.236.231; 2.E.236.236; 2.E.236.237;2.E.236.238; 2.E.236.239; 2.E.236.154; 2.E.236.157; 2.E.236.166;2.E.236.169; 2.E.236.172; 2.E.236.175; 2.E.236.240; 2.E.236.244;2.E.237.228; 2.E.237.229; 2.E.237.230; 2.E.237.231; 2.E.237.236;2.E.237.237; 2.E.237.238; 2.E.237.239; 2.E.237.154; 2.E.237.157;2.E.237.166; 2.E.237.169; 2.E.237.172; 2.E.237.175; 2.E.237.240;2.E.237.244; 2.E.238.228; 2.E.238.229; 2.E.238.230; 2.E.238.231;2.E.238.236; 2.E.238.237; 2.E.238.238; 2.E.238.239; 2.E.238.154;2.E.238.157; 2.E.238.166; 2.E.238.169; 2.E.238.172; 2.E.238.175;2.E.238.240; 2.E.238.244; 2.E.239.228; 2.E.239.229; 2.E.239.230;2.E.239.231; 2.E.239.236; 2.E.239.237; 2.E.239.238; 2.E.239.239;2.E.239.154; 2.E.239.157; 2.E.239.166; 2.E.239.169; 2.E.239.172;2.E.239.175; 2.E.239.240; 2.E.239.244; 2.E.154.228; 2.E.154.229;2.E.154.230; 2.E.154.231; 2.E.154.236; 2.E.154.237; 2.E.154.238;2.E.154.239; 2.E.154.154; 2.E.154.157; 2.E.154.166; 2.E.154.169;2.E.154.172; 2.E.154.175; 2.E.154.240; 2.E.154.244; 2.E.157.228;2.E.157.229; 2.E.157.230; 2.E.157.231; 2.E.157.236; 2.E.157.237;2.E.157.238; 2.E.157.239; 2.E.157.154; 2.E.157.157; 2.E.157.166;2.E.157.169; 2.E.157.172; 2.E.157.175; 2.E.157.240; 2.E.157.244;2.E.166.228; 2.E.166.229; 2.E.166.230; 2.E.166.231; 2.E.166.236;2.E.166.237; 2.E.166.238; 2.E.166.239; 2.E.166.154; 2.E.166.157;2.E.166.166; 2.E.166.169; 2.E.166.172; 2.E.166.175; 2.E.166.240;2.E.166.244; 2.E.169.228; 2.E.169.229; 2.E.169.230; 2.E.169.231;2.E.169.236; 2.E.169.237; 2.E.169.238; 2.E.169.239; 2.E.169.154;2.E.169.157; 2.E.169.166; 2.E.169.169; 2.E.169.172; 2.E.169.175;2.E.169.240; 2.E.169.244; 2.E.172.228; 2.E.172.229; 2.E.172.230;2.E.172.231; 2.E.172.236; 2.E.172.237; 2.E.172.238; 2.E.172.239;2.E.172.154; 2.E.172.157; 2.E.172.166; 2.E.172.169; 2.E.172.172;2.E.172.175; 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2.I.244.239; 2.I.244.154; 2.I.244.157; 2.I.244.166;2.I.244.169; 2.I.244.172; 2.I.244.175; 2.I.244.240; 2.I.244.244;Prodrugs of 2.J 2.J.228.228; 2.J.228.229; 2.J.228.230; 2.J.228.231;2.J.228.236; 2.J.228.237; 2.J.228.238; 2.J.228.239; 2.J.228.154;2.J.228.157; 2.J.228.166; 2.J.228.169; 2.J.228.172; 2.J.228.175;2.J.228.240; 2.J.228.244; 2.J.229.228; 2.J.229.229; 2.J.229.230;2.J.229.231; 2.J.229.236; 2.J.229.237; 2.J.229.238; 2.J.229.239;2.J.229.154; 2.J.229.157; 2.J.229.166; 2.J.229.169; 2.J.229.172;2.J.229.175; 2.J.229.240; 2.J.229.244; 2.J.230.228; 2.J.230.229;2.J.230.230; 2.J.230.231; 2.J.230.236; 2.J.230.237; 2.J.230.238;2.J.230.239; 2.J.230.154; 2.J.230.157; 2.J.230.166; 2.J.230.169;2.J.230.172; 2.J.230.175; 2.J.230.240; 2.J.230.244; 2.J.231.228;2.J.231.229; 2.J.231.230; 2.J.231.231; 2.J.231.236; 2.J.231.237;2.J.231.238; 2.J.231.239; 2.J.231.154; 2.J.231.157; 2.J.231.166;2.J.231.169; 2.J.231.172; 2.J.231.175; 2.J.231.240; 2.J.231.244;2.J.236.228; 2.J.236.229; 2.J.236.230; 2.J.236.231; 2.J.236.236;2.J.236.237; 2.J.236.238; 2.J.236.239; 2.J.236.154; 2.J.236.157;2.J.236.166; 2.J.236.169; 2.J.236.172; 2.J.236.175; 2.J.236.240;2.J.236.244; 2.J.237.228; 2.J.237.229; 2.J.237.230; 2.J.237.231;2.J.237.236; 2.J.237.237; 2.J.237.238; 2.J.237.239; 2.J.237.154;2.J.237.157; 2.J.237.166; 2.J.237.169; 2.J.237.172; 2.J.237.175;2.J.237.240; 2.J.237.244; 2.J.238.228; 2.J.238.229; 2.J.238.230;2.J.238.231; 2.J.238.236; 2.J.238.237; 2.J.238.238; 2.J.238.239;2.J.238.154; 2.J.238.157; 2.J.238.166; 2.J.238.169; 2.J.238.172;2.J.238.175; 2.J.238.240; 2.J.238.244; 2.J.239.228; 2.J.239.229;2.J.239.230; 2.J.239.231; 2.J.239.236; 2.J.239.237; 2.J.239.238;2.J.239.239; 2.J.239.154; 2.J.239.157; 2.J.239.166; 2.J.239.169;2.J.239.172; 2.J.239.175; 2.J.239.240; 2.J.239.244; 2.J.154.228;2.J.154.229; 2.J.154.230; 2.J.154.231; 2.J.154.236; 2.J.154.237;2.J.154.238; 2.J.154.239; 2.J.154.154; 2.J.154.157; 2.J.154.166;2.J.154.169; 2.J.154.172; 2.J.154.175; 2.J.154.240; 2.J.154.244;2.J.157.228; 2.J.157.229; 2.J.157.230; 2.J.157.231; 2.J.157.236;2.J.157.237; 2.J.157.238; 2.J.157.239; 2.J.157.154; 2.J.157.157;2.J.157.166; 2.J.157.169; 2.J.157.172; 2.J.157.175; 2.J.157.240;2.J.157.244; 2.J.166.228; 2.J.166.229; 2.J.166.230; 2.J.166.231;2.J.166.236; 2.J.166.237; 2.J.166.238; 2.J.166.239; 2.J.166.154;2.J.166.157; 2.J.166.166; 2.J.166.169; 2.J.166.172; 2.J.166.175;2.J.166.240; 2.J.166.244; 2.J.169.228; 2.J.169.229; 2.J.169.230;2.J.169.231; 2.J.169.236; 2.J.169.237; 2.J.169.238; 2.J.169.239;2.J.169.154; 2.J.169.157; 2.J.169.166; 2.J.169.169; 2.J.169.172;2.J.169.175; 2.J.169.240; 2.J.169.244; 2.J.172.228; 2.J.172.229;2.J.172.230; 2.J.172.231; 2.J.172.236; 2.J.172.237; 2.J.172.238;2.J.172.239; 2.J.172.154; 2.J.172.157; 2.J.172.166; 2.J.172.169;2.J.172.172; 2.J.172.175; 2.J.172.240; 2.J.172.244; 2.J.175.228;2.J.175.229; 2.J.175.230; 2.J.175.231; 2.J.175.236; 2.J.175.237;2.J.175.238; 2.J.175.239; 2.J.175.154; 2.J.175.157; 2.J.175.166;2.J.175.169; 2.J.175.172; 2.J.175.175; 2.J.175.240; 2.J.175.244;2.J.240.228; 2.J.240.229; 2.J.240.230; 2.J.240.231; 2.J.240.236;2.J.240.237; 2.J.240.238; 2.J.240.239; 2.J.240.154; 2.J.240.157;2.J.240.166; 2.J.240.169; 2.J.240.172; 2.J.240.175; 2.J.240.240;2.J.240.244; 2.J.244.228; 2.J.244.229; 2.J.244.230; 2.J.244.231;2.J.244.236; 2.J.244.237; 2.J.244.238; 2.J.244.239; 2.J.244.154;2.J.244.157; 2.J.244.166; 2.J.244.169; 2.J.244.172; 2.J.244.175;2.J.244.240; 2.J.244.244; Prodrugs of 2.L 2.L.228.228; 2.L.228.229;2.L.228.230; 2.L.228.231; 2.L.228.236; 2.L.228.237; 2.L.228.238;2.L.228.239; 2.L.228.154; 2.L.228.157; 2.L.228.166; 2.L.228.169;2.L.228.172; 2.L.228.175; 2.L.228.240; 2.L.228.244; 2.L.229.228;2.L.229.229; 2.L.229.230; 2.L.229.231; 2.L.229.236; 2.L.229.237;2.L.229.238; 2.L.229.239; 2.L.229.154; 2.L.229.157; 2.L.229.166;2.L.229.169; 2.L.229.172; 2.L.229.175; 2.L.229.240; 2.L.229.244;2.L.230.228; 2.L.230.229; 2.L.230.230; 2.L.230.231; 2.L.230.236;2.L.230.237; 2.L.230.238; 2.L.230.239; 2.L.230.154; 2.L.230.157;2.L.230.166; 2.L.230.169; 2.L.230.172; 2.L.230.175; 2.L.230.240;2.L.230.244; 2.L.231.228; 2.L.231.229; 2.L.231.230; 2.L.231.231;2.L.231.236; 2.L.231.237; 2.L.231.238; 2.L.231.239; 2.L.231.154;2.L.231.157; 2.L.231.166; 2.L.231.169; 2.L.231.172; 2.L.231.175;2.L.231.240; 2.L.231.244; 2.L.236.228; 2.L.236.229; 2.L.236.230;2.L.236.231; 2.L.236.236; 2.L.236.237; 2.L.236.238; 2.L.236.239;2.L.236.154; 2.L.236.157; 2.L.236.166; 2.L.236.169; 2.L.236.172;2.L.236.175; 2.L.236.240; 2.L.236.244; 2.L.237.228; 2.L.237.229;2.L.237.230; 2.L.237.231; 2.L.237.236; 2.L.237.237; 2.L.237.238;2.L.237.239; 2.L.237.154; 2.L.237.157; 2.L.237.166; 2.L.237.169;2.L.237.172; 2.L.237.175; 2.L.237.240; 2.L.237.244; 2.L.238.228;2.L.238.229; 2.L.238.230; 2.L.238.231; 2.L.238.236; 2.L.238.237;2.L.238.238; 2.L.238.239; 2.L.238.154; 2.L.238.157; 2.L.238.166;2.L.238.169; 2.L.238.172; 2.L.238.175; 2.L.238.240; 2.L.238.244;2.L.239.228; 2.L.239.229; 2.L.239.230; 2.L.239.231; 2.L.239.236;2.L.239.237; 2.L.239.238; 2.L.239.239; 2.L.239.154; 2.L.239.157;2.L.239.166; 2.L.239.169; 2.L.239.172; 2.L.239.175; 2.L.239.240;2.L.239.244; 2.L.154.228; 2.L.154.229; 2.L.154.230; 2.L.154.231;2.L.154.236; 2.L.154.237; 2.L.154.238; 2.L.154.239; 2.L.154.154;2.L.154.157; 2.L.154.166; 2.L.154.169; 2.L.154.172; 2.L.154.175;2.L.154.240; 2.L.154.244; 2.L.157.228; 2.L.157.229; 2.L.157.230;2.L.157.231; 2.L.157.236; 2.L.157.237; 2.L.157.238; 2.L.157.239;2.L.157.154; 2.L.157.157; 2.L.157.166; 2.L.157.169; 2.L.157.172;2.L.157.175; 2.L.157.240; 2.L.157.244; 2.L.166.228; 2.L.166.229;2.L.166.230; 2.L.166.231; 2.L.166.236; 2.L.166.237; 2.L.166.238;2.L.166.239; 2.L.166.154; 2.L.166.157; 2.L.166.166; 2.L.166.169;2.L.166.172; 2.L.166.175; 2.L.166.240; 2.L.166.244; 2.L.169.228;2.L.169.229; 2.L.169.230; 2.L.169.231; 2.L.169.236; 2.L.169.237;2.L.169.238; 2.L.169.239; 2.L.169.154; 2.L.169.157; 2.L.169.166;2.L.169.169; 2.L.169.172; 2.L.169.175; 2.L.169.240; 2.L.169.244;2.L.172.228; 2.L.172.229; 2.L.172.230; 2.L.172.231; 2.L.172.236;2.L.172.237; 2.L.172.238; 2.L.172.239; 2.L.172.154; 2.L.172.157;2.L.172.166; 2.L.172.169; 2.L.172.172; 2.L.172.175; 2.L.172.240;2.L.172.244; 2.L.175.228; 2.L.175.229; 2.L.175.230; 2.L.175.231;2.L.175.236; 2.L.175.237; 2.L.175.238; 2.L.175.239; 2.L.175.154;2.L.175.157; 2.L.175.166; 2.L.175.169; 2.L.175.172; 2.L.175.175;2.L.175.240; 2.L.175.244; 2.L.240.228; 2.L.240.229; 2.L.240.230;2.L.240.231; 2.L.240.236; 2.L.240.237; 2.L.240.238; 2.L.240.239;2.L.240.154; 2.L.240.157; 2.L.240.166; 2.L.240.169; 2.L.240.172;2.L.240.175; 2.L.240.240; 2.L.240.244; 2.L.244.228; 2.L.244.229;2.L.244.230; 2.L.244.231; 2.L.244.236; 2.L.244.237; 2.L.244.238;2.L.244.239; 2.L.244.154; 2.L.244.157; 2.L.244.166; 2.L.244.169;2.L.244.172; 2.L.244.175; 2.L.244.240; 2.L.244.244; Prodrugs of 2.O2.O.228.228; 2.O.228.229; 2.O.228.230; 2.O.228.231; 2.O.228.236;2.O.228.237; 2.O.228.238; 2.O.228.239; 2.O.228.154; 2.O.228.157;2.O.228.166; 2.O.228.169; 2.O.228.172; 2.O.228.175; 2.O.228.240;2.O.228.244; 2.O.229.228; 2.O.229.229; 2.O.229.230; 2.O.229.231;2.O.229.236; 2.O.229.237; 2.O.229.238; 2.O.229.239; 2.O.229.154;2.O.229.157; 2.O.229.166; 2.O.229.169; 2.O.229.172; 2.O.229.175;2.O.229.240; 2.O.229.244; 2.O.230.228; 2.O.230.229; 2.O.230.230;2.O.230.231; 2.O.230.236; 2.O.230.237; 2.O.230.238; 2.O.230.239;2.O.230.154; 2.O.230.157; 2.O.230.166; 2.O.230.169; 2.O.230.172;2.O.230.175; 2.O.230.240; 2.O.230.244; 2.O.231.228; 2.O.231.229;2.O.231.230; 2.O.231.231; 2.O.231.236; 2.O.231.237; 2.O.231.238;2.O.231.239; 2.O.231.154; 2.O.231.157; 2.O.231.166; 2.O.231.169;2.O.231.172; 2.O.231.175; 2.O.231.240; 2.O.231.244; 2.O.236.228;2.O.236.229; 2.O.236.230; 2.O.236.231; 2.O.236.236; 2.O.236.237;2.O.236.238; 2.O.236.239; 2.O.236.154; 2.O.236.157; 2.O.236.166;2.O.236.169; 2.O.236.172; 2.O.236.175; 2.O.236.240; 2.O.236.244;2.O.237.228; 2.O.237.229; 2.O.237.230; 2.O.237.231; 2.O.237.236;2.O.237.237; 2.O.237.238; 2.O.237.239; 2.O.237.154; 2.O.237.157;2.O.237.166; 2.O.237.169; 2.O.237.172; 2.O.237.175; 2.O.237.240;2.O.237.244; 2.O.238.228; 2.O.238.229; 2.O.238.230; 2.O.238.231;2.O.238.236; 2.O.238.237; 2.O.238.238; 2.O.238.239; 2.O.238.154;2.O.238.157; 2.O.238.166; 2.O.238.169; 2.O.238.172; 2.O.238.175;2.O.238.240; 2.O.238.244; 2.O.239.228; 2.O.239.229; 2.O.239.230;2.O.239.231; 2.O.239.236; 2.O.239.237; 2.O.239.238; 2.O.239.239;2.O.239.154; 2.O.239.157; 2.O.239.166; 2.O.239.169; 2.O.239.172;2.O.239.175; 2.O.239.240; 2.O.239.244; 2.O.154.228; 2.O.154.229;2.O.154.230; 2.O.154.231; 2.O.154.236; 2.O.154.237; 2.O.154.238;2.O.154.239; 2.O.154.154; 2.O.154.157; 2.O.154.166; 2.O.154.169;2.O.154.172; 2.O.154.175; 2.O.154.240; 2.O.154.244; 2.O.157.228;2.O.157.229; 2.O.157.230; 2.O.157.231; 2.O.157.236; 2.O.157.237;2.O.157.238; 2.O.157.239; 2.O.157.154; 2.O.157.157; 2.O.157.166;2.O.157.169; 2.O.157.172; 2.O.157.175; 2.O.157.240; 2.O.157.244;2.O.166.228; 2.O.166.229; 2.O.166.230; 2.O.166.231; 2.O.166.236;2.O.166.237; 2.O.166.238; 2.O.166.239; 2.O.166.154; 2.O.166.157;2.O.166.166; 2.O.166.169; 2.O.166.172; 2.O.166.175; 2.O.166.240;2.O.166.244; 2.O.169.228; 2.O.169.229; 2.O.169.230; 2.O.169.231;2.O.169.236; 2.O.169.237; 2.O.169.238; 2.O.169.239; 2.O.169.154;2.O.169.157; 2.O.169.166; 2.O.169.169; 2.O.169.172; 2.O.169.175;2.O.169.240; 2.O.169.244; 2.O.172.228; 2.O.172.229; 2.O.172.230;2.O.172.231; 2.O.172.236; 2.O.172.237; 2.O.172.238; 2.O.172.239;2.O.172.154; 2.O.172.157; 2.O.172.166; 2.O.172.169; 2.O.172.172;2.O.172.175; 2.O.172.240; 2.O.172.244; 2.O.175.228; 2.O.175.229;2.O.175.230; 2.O.175.231; 2.O.175.236; 2.O.175.237; 2.O.175.238;2.O.175.239; 2.O.175.154; 2.O.175.157; 2.O.175.166; 2.O.175.169;2.O.175.172; 2.O.175.175; 2.O.175.240; 2.O.175.244; 2.O.240.228;2.O.240.229; 2.O.240.230; 2.O.240.231; 2.O.240.236; 2.O.240.237;2.O.240.238; 2.O.240.239; 2.O.240.154; 2.O.240.157; 2.O.240.166;2.O.240.169; 2.O.240.172; 2.O.240.175; 2.O.240.240; 2.O.240.244;2.O.244.228; 2.O.244.229; 2.O.244.230; 2.O.244.231; 2.O.244.236;2.O.244.237; 2.O.244.238; 2.O.244.239; 2.O.244.154; 2.O.244.157;2.O.244.166; 2.O.244.169; 2.O.244.172; 2.O.244.175; 2.O.244.240;2.O.244.244; Prodrugs of 2.P 2.P.228.228; 2.P.228.229; 2.P.228.230;2.P.228.231; 2.P.228.236; 2.P.228.237; 2.P.228.238; 2.P.228.239;2.P.228.154; 2.P.228.157; 2.P.228.166; 2.P.228.169; 2.P.228.172;2.P.228.175; 2.P.228.240; 2.P.228.244; 2.P.229.228; 2.P.229.229;2.P.229.230; 2.P.229.231; 2.P.229.236; 2.P.229.237; 2.P.229.238;2.P.229.239; 2.P.229.154; 2.P.229.157; 2.P.229.166; 2.P.229.169;2.P.229.172; 2.P.229.175; 2.P.229.240; 2.P.229.244; 2.P.230.228;2.P.230.229; 2.P.230.230; 2.P.230.231; 2.P.230.236; 2.P.230.237;2.P.230.238; 2.P.230.239; 2.P.230.154; 2.P.230.157; 2.P.230.166;2.P.230.169; 2.P.230.172; 2.P.230.175; 2.P.230.240; 2.P.230.244;2.P.231.228; 2.P.231.229; 2.P.231.230; 2.P.231.231; 2.P.231.236;2.P.231.237; 2.P.231.238; 2.P.231.239; 2.P.231.154; 2.P.231.157;2.P.231.166; 2.P.231.169; 2.P.231.172; 2.P.231.175; 2.P.231.240;2.P.231.244; 2.P.236.228; 2.P.236.229; 2.P.236.230; 2.P.236.231;2.P.236.236; 2.P.236.237; 2.P.236.238; 2.P.236.239; 2.P.236.154;2.P.236.157; 2.P.236.166; 2.P.236.169; 2.P.236.172; 2.P.236.175;2.P.236.240; 2.P.236.244; 2.P.237.228; 2.P.237.229; 2.P.237.230;2.P.237.231; 2.P.237.236; 2.P.237.237; 2.P.237.238; 2.P.237.239;2.P.237.154; 2.P.237.157; 2.P.237.166; 2.P.237.169; 2.P.237.172;2.P.237.175; 2.P.237.240; 2.P.237.244; 2.P.238.228; 2.P.238.229;2.P.238.230; 2.P.238.231; 2.P.238.236; 2.P.238.237; 2.P.238.238;2.P.238.239; 2.P.238.154; 2.P.238.157; 2.P.238.166; 2.P.238.169;2.P.238.172; 2.P.238.175; 2.P.238.240; 2.P.238.244; 2.P.239.228;2.P.239.229; 2.P.239.230; 2.P.239.231; 2.P.239.236; 2.P.239.237;2.P.239.238; 2.P.239.239; 2.P.239.154; 2.P.239.157; 2.P.239.166;2.P.239.169; 2.P.239.172; 2.P.239.175; 2.P.239.240; 2.P.239.244;2.P.154.228; 2.P.154.229; 2.P.154.230; 2.P.154.231; 2.P.154.236;2.P.154.237; 2.P.154.238; 2.P.154.239; 2.P.154.154; 2.P.154.157;2.P.154.166; 2.P.154.169; 2.P.154.172; 2.P.154.175; 2.P.154.240;2.P.154.244; 2.P.157.228; 2.P.157.229; 2.P.157.230; 2.P.157.231;2.P.157.236; 2.P.157.237; 2.P.157.238; 2.P.157.239; 2.P.157.154;2.P.157.157; 2.P.157.166; 2.P.157.169; 2.P.157.172; 2.P.157.175;2.P.157.240; 2.P.157.244; 2.P.166.228; 2.P.166.229; 2.P.166.230;2.P.166.231; 2.P.166.236; 2.P.166.237; 2.P.166.238; 2.P.166.239;2.P.166.154; 2.P.166.157; 2.P.166.166; 2.P.166.169; 2.P.166.172;2.P.166.175; 2.P.166.240; 2.P.166.244; 2.P.169.228; 2.P.169.229;2.P.169.230; 2.P.169.231; 2.P.169.236; 2.P.169.237; 2.P.169.238;2.P.169.239; 2.P.169.154; 2.P.169.157; 2.P.169.166; 2.P.169.169;2.P.169.172; 2.P.169.175; 2.P.169.240; 2.P.169.244; 2.P.172.228;2.P.172.229; 2.P.172.230; 2.P.172.231; 2.P.172.236; 2.P.172.237;2.P.172.238; 2.P.172.239; 2.P.172.154; 2.P.172.157; 2.P.172.166;2.P.172.169; 2.P.172.172; 2.P.172.175; 2.P.172.240; 2.P.172.244;2.P.175.228; 2.P.175.229; 2.P.175.230; 2.P.175.231; 2.P.175.236;2.P.175.237; 2.P.175.238; 2.P.175.239; 2.P.175.154; 2.P.175.157;2.P.175.166; 2.P.175.169; 2.P.175.172; 2.P.175.175; 2.P.175.240;2.P.175.244; 2.P.240.228; 2.P.240.229; 2.P.240.230; 2.P.240.231;2.P.240.236; 2.P.240.237; 2.P.240.238; 2.P.240.239; 2.P.240.154;2.P.240.157; 2.P.240.166; 2.P.240.169; 2.P.240.172; 2.P.240.175;2.P.240.240; 2.P.240.244; 2.P.244.228; 2.P.244.229; 2.P.244.230;2.P.244.231; 2.P.244.236; 2.P.244.237; 2.P.244.238; 2.P.244.239;2.P.244.154; 2.P.244.157; 2.P.244.166; 2.P.244.169; 2.P.244.172;2.P.244.175; 2.P.244.240; 2.P.244.244; Prodrugs of 2.U 2.U.228.228;2.U.228.229; 2.U.228.230; 2.U.228.231; 2.U.228.236; 2.U.228.237;2.U.228.238; 2.U.228.239; 2.U.228.154; 2.U.228.157; 2.U.228.166;2.U.228.169; 2.U.228.172; 2.U.228.175; 2.U.228.240; 2.U.228.244;2.U.229.228; 2.U.229.229; 2.U.229.230; 2.U.229.231; 2.U.229.236;2.U.229.237; 2.U.229.238; 2.U.229.239; 2.U.229.154; 2.U.229.157;2.U.229.166; 2.U.229.169; 2.U.229.172; 2.U.229.175; 2.U.229.240;2.U.229.244; 2.U.230.228; 2.U.230.229; 2.U.230.230; 2.U.230.231;2.U.230.236; 2.U.230.237; 2.U.230.238; 2.U.230.239; 2.U.230.154;2.U.230.157; 2.U.230.166; 2.U.230.169; 2.U.230.172; 2.U.230.175;2.U.230.240; 2.U.230.244; 2.U.231.228; 2.U.231.229; 2.U.231.230;2.U.231.231; 2.U.231.236; 2.U.231.237; 2.U.231.238; 2.U.231.239;2.U.231.154; 2.U.231.157; 2.U.231.166; 2.U.231.169; 2.U.231.172;2.U.231.175; 2.U.231.240; 2.U.231.244; 2.U.236.228; 2.U.236.229;2.U.236.230; 2.U.236.231; 2.U.236.236; 2.U.236.237; 2.U.236.238;2.U.236.239; 2.U.236.154; 2.U.236.157; 2.U.236.166; 2.U.236.169;2.U.236.172; 2.U.236.175; 2.U.236.240; 2.U.236.244; 2.U.237.228;2.U.237.229; 2.U.237.230; 2.U.237.231; 2.U.237.236; 2.U.237.237;2.U.237.238; 2.U.237.239; 2.U.237.154; 2.U.237.157; 2.U.237.166;2.U.237.169; 2.U.237.172; 2.U.237.175; 2.U.237.240; 2.U.237.244;2.U.238.228; 2.U.238.229; 2.U.238.230; 2.U.238.231; 2.U.238.236;2.U.238.237; 2.U.238.238; 2.U.238.239; 2.U.238.154; 2.U.238.157;2.U.238.166; 2.U.238.169; 2.U.238.172; 2.U.238.175; 2.U.238.240;2.U.238.244; 2.U.239.228; 2.U.239.229; 2.U.239.230; 2.U.239.231;2.U.239.236; 2.U.239.237; 2.U.239.238; 2.U.239.239; 2.U.239.154;2.U.239.157; 2.U.239.166; 2.U.239.169; 2.U.239.172; 2.U.239.175;2.U.239.240; 2.U.239.244; 2.U.154.228; 2.U.154.229; 2.U.154.230;2.U.154.231; 2.U.154.236; 2.U.154.237; 2.U.154.238; 2.U.154.239;2.U.154.154; 2.U.154.157; 2.U.154.166; 2.U.154.169; 2.U.154.172;2.U.154.175; 2.U.154.240; 2.U.154.244; 2.U.157.228; 2.U.157.229;2.U.157.230; 2.U.157.231; 2.U.157.236; 2.U.157.237; 2.U.157.238;2.U.157.239; 2.U.157.154; 2.U.157.157; 2.U.157.166; 2.U.157.169;2.U.157.172; 2.U.157.175; 2.U.157.240; 2.U.157.244; 2.U.166.228;2.U.166.229; 2.U.166.230; 2.U.166.231; 2.U.166.236; 2.U.166.237;2.U.166.238; 2.U.166.239; 2.U.166.154; 2.U.166.157; 2.U.166.166;2.U.166.169; 2.U.166.172; 2.U.166.175; 2.U.166.240; 2.U.166.244;2.U.169.228; 2.U.169.229; 2.U.169.230; 2.U.169.231; 2.U.169.236;2.U.169.237; 2.U.169.238; 2.U.169.239; 2.U.169.154; 2.U.169.157;2.U.169.166; 2.U.169.169; 2.U.169.172; 2.U.169.175; 2.U.169.240;2.U.169.244; 2.U.172.228; 2.U.172.229; 2.U.172.230; 2.U.172.231;2.U.172.236; 2.U.172.237; 2.U.172.238; 2.U.172.239; 2.U.172.154;2.U.172.157; 2.U.172.166; 2.U.172.169; 2.U.172.172; 2.U.172.175;2.U.172.240; 2.U.172.244; 2.U.175.228; 2.U.175.229; 2.U.175.230;2.U.175.231; 2.U.175.236; 2.U.175.237; 2.U.175.238; 2.U.175.239;2.U.175.154; 2.U.175.157; 2.U.175.166; 2.U.175.169; 2.U.175.172;2.U.175.175; 2.U.175.240; 2.U.175.244; 2.U.240.228; 2.U.240.229;2.U.240.230; 2.U.240.231; 2.U.240.236; 2.U.240.237; 2.U.240.238;2.U.240.239; 2.U.240.154; 2.U.240.157; 2.U.240.166; 2.U.240.169;2.U.240.172; 2.U.240.175; 2.U.240.240; 2.U.240.244; 2.U.244.228;2.U.244.229; 2.U.244.230; 2.U.244.231; 2.U.244.236; 2.U.244.237;2.U.244.238; 2.U.244.239; 2.U.244.154; 2.U.244.157; 2.U.244.166;2.U.244.169; 2.U.244.172; 2.U.244.175; 2.U.244.240; 2.U.244.244;Prodrugs of 2.W 2.W.228.228; 2.W.228.229; 2.W.228.230; 2.W.228.231;2.W.228.236; 2.W.228.237; 2.W.228.238; 2.W.228.239; 2.W.228.154;2.W.228.157; 2.W.228.166; 2.W.228.169; 2.W.228.172; 2.W.228.175;2.W.228.240; 2.W.228.244; 2.W.229.228; 2.W.229.229; 2.W.229.230;2.W.229.231; 2.W.229.236; 2.W.229.237; 2.W.229.238; 2.W.229.239;2.W.229.154; 2.W.229.157; 2.W.229.166; 2.W.229.169; 2.W.229.172;2.W.229.175; 2.W.229.240; 2.W.229.244; 2.W.230.228; 2.W.230.229;2.W.230.230; 2.W.230.231; 2.W.230.236; 2.W.230.237; 2.W.230.238;2.W.230.239; 2.W.230.154; 2.W.230.157; 2.W.230.166; 2.W.230.169;2.W.230.172; 2.W.230.175; 2.W.230.240; 2.W.230.244; 2.W.231.228;2.W.231.229; 2.W.231.230; 2.W.231.231; 2.W.231.236; 2.W.231.237;2.W.231.238; 2.W.231.239; 2.W.231.154; 2.W.231.157; 2.W.231.166;2.W.231.169; 2.W.231.172; 2.W.231.175; 2.W.231.240; 2.W.231.244;2.W.236.228; 2.W.236.229; 2.W.236.230; 2.W.236.231; 2.W.236.236;2.W.236.237; 2.W.236.238; 2.W.236.239; 2.W.236.154; 2.W.236.157;2.W.236.166; 2.W.236.169; 2.W.236.172; 2.W.236.175; 2.W.236.240;2.W.236.244; 2.W.237.228; 2.W.237.229; 2.W.237.230; 2.W.237.231;2.W.237.236; 2.W.237.237; 2.W.237.238; 2.W.237.239; 2.W.237.154;2.W.237.157; 2.W.237.166; 2.W.237.169; 2.W.237.172; 2.W.237.175;2.W.237.240; 2.W.237.244; 2.W.238.228; 2.W.238.229; 2.W.238.230;2.W.238.231; 2.W.238.236; 2.W.238.237; 2.W.238.238; 2.W.238.239;2.W.238.154; 2.W.238.157; 2.W.238.166; 2.W.238.169; 2.W.238.172;2.W.238.175; 2.W.238.240; 2.W.238.244; 2.W.239.228; 2.W.239.229;2.W.239.230; 2.W.239.231; 2.W.239.236; 2.W.239.237; 2.W.239.238;2.W.239.239; 2.W.239.154; 2.W.239.157; 2.W.239.166; 2.W.239.169;2.W.239.172; 2.W.239.175; 2.W.239.240; 2.W.239.244; 2.W.154.228;2.W.154.229; 2.W.154.230; 2.W.154.231; 2.W.154.236; 2.W.154.237;2.W.154.238; 2.W.154.239; 2.W.154.154; 2.W.154.157; 2.W.154.166;2.W.154.169; 2.W.154.172; 2.W.154.175; 2.W.154.240; 2.W.154.244;2.W.157.228; 2.W.157.229; 2.W.157.230; 2.W.157.231; 2.W.157.236;2.W.157.237; 2.W.157.238; 2.W.157.239; 2.W.157.154; 2.W.157.157;2.W.157.166; 2.W.157.169; 2.W.157.172; 2.W.157.175; 2.W.157.240;2.W.157.244; 2.W.166.228; 2.W.166.229; 2.W.166.230; 2.W.166.231;2.W.166.236; 2.W.166.237; 2.W.166.238; 2.W.166.239; 2.W.166.154;2.W.166.157; 2.W.166.166; 2.W.166.169; 2.W.166.172; 2.W.166.175;2.W.166.240; 2.W.166.244; 2.W.169.228; 2.W.169.229; 2.W.169.230;2.W.169.231; 2.W.169.236; 2.W.169.237; 2.W.169.238; 2.W.169.239;2.W.169.154; 2.W.169.157; 2.W.169.166; 2.W.169.169; 2.W.169.172;2.W.169.175; 2.W.169.240; 2.W.169.244; 2.W.172.228; 2.W.172.229;2.W.172.230; 2.W.172.231; 2.W.172.236; 2.W.172.237; 2.W.172.238;2.W.172.239; 2.W.172.154; 2.W.172.157; 2.W.172.166; 2.W.172.169;2.W.172.172; 2.W.172.175; 2.W.172.240; 2.W.172.244; 2.W.175.228;2.W.175.229; 2.W.175.230; 2.W.175.231; 2.W.175.236; 2.W.175.237;2.W.175.238; 2.W.175.239; 2.W.175.154; 2.W.175.157; 2.W.175.166;2.W.175.169; 2.W.175.172; 2.W.175.175; 2.W.175.240; 2.W.175.244;2.W.240.228; 2.W.240.229; 2.W.240.230; 2.W.240.231; 2.W.240.236;2.W.240.237; 2.W.240.238; 2.W.240.239; 2.W.240.154; 2.W.240.157;2.W.240.166; 2.W.240.169; 2.W.240.172; 2.W.240.175; 2.W.240.240;2.W.240.244; 2.W.244.228; 2.W.244.229; 2.W.244.230; 2.W.244.231;2.W.244.236; 2.W.244.237; 2.W.244.238; 2.W.244.239; 2.W.244.154;2.W.244.157; 2.W.244.166; 2.W.244.169; 2.W.244.172; 2.W.244.175;2.W.244.240; 2.W.244.244; Prodrugs of 2.Y 2.Y.228.228; 2.Y.228.229;2.Y.228.230; 2.Y.228.231; 2.Y.228.236; 2.Y.228.237; 2.Y.228.238;2.Y.228.239; 2.Y.228.154; 2.Y.228.157; 2.Y.228.166; 2.Y.228.169;2.Y.228.172; 2.Y.228.175; 2.Y.228.240; 2.Y.228.244; 2.Y.229.228;2.Y.229.229; 2.Y.229.230; 2.Y.229.231; 2.Y.229.236; 2.Y.229.237;2.Y.229.238; 2.Y.229.239; 2.Y.229.154; 2.Y.229.157; 2.Y.229.166;2.Y.229.169; 2.Y.229.172; 2.Y.229.175; 2.Y.229.240; 2.Y.229.244;2.Y.230.228; 2.Y.230.229; 2.Y.230.230; 2.Y.230.231; 2.Y.230.236;2.Y.230.237; 2.Y.230.238; 2.Y.230.239; 2.Y.230.154; 2.Y.230.157;2.Y.230.166; 2.Y.230.169; 2.Y.230.172; 2.Y.230.175; 2.Y.230.240;2.Y.230.244; 2.Y.231.228; 2.Y.231.229; 2.Y.231.230; 2.Y.231.231;2.Y.231.236; 2.Y.231.237; 2.Y.231.238; 2.Y.231.239; 2.Y.231.154;2.Y.231.157; 2.Y.231.166; 2.Y.231.169; 2.Y.231.172; 2.Y.231.175;2.Y.231.240; 2.Y.231.244; 2.Y.236.228; 2.Y.236.229; 2.Y.236.230;2.Y.236.231; 2.Y.236.236; 2.Y.236.237; 2.Y.236.238; 2.Y.236.239;2.Y.236.154; 2.Y.236.157; 2.Y.236.166; 2.Y.236.169; 2.Y.236.172;2.Y.236.175; 2.Y.236.240; 2.Y.236.244; 2.Y.237.228; 2.Y.237.229;2.Y.237.230; 2.Y.237.231; 2.Y.237.236; 2.Y.237.237; 2.Y.237.238;2.Y.237.239; 2.Y.237.154; 2.Y.237.157; 2.Y.237.166; 2.Y.237.169;2.Y.237.172; 2.Y.237.175; 2.Y.237.240; 2.Y.237.244; 2.Y.238.228;2.Y.238.229; 2.Y.238.230; 2.Y.238.231; 2.Y.238.236; 2.Y.238.237;2.Y.238.238; 2.Y.238.239; 2.Y.238.154; 2.Y.238.157; 2.Y.238.166;2.Y.238.169; 2.Y.238.172; 2.Y.238.175; 2.Y.238.240; 2.Y.238.244;2.Y.239.228; 2.Y.239.229; 2.Y.239.230; 2.Y.239.231; 2.Y.239.236;2.Y.239.237; 2.Y.239.238; 2.Y.239.239; 2.Y.239.154; 2.Y.239.157;2.Y.239.166; 2.Y.239.169; 2.Y.239.172; 2.Y.239.175; 2.Y.239.240;2.Y.239.244; 2.Y.154.228; 2.Y.154.229; 2.Y.154.230; 2.Y.154.231;2.Y.154.236; 2.Y.154.237; 2.Y.154.238; 2.Y.154.239; 2.Y.154.154;2.Y.154.157; 2.Y.154.166; 2.Y.154.169; 2.Y.154.172; 2.Y.154.175;2.Y.154.240; 2.Y.154.244; 2.Y.157.228; 2.Y.157.229; 2.Y.157.230;2.Y.157.231; 2.Y.157.236; 2.Y.157.237; 2.Y.157.238; 2.Y.157.239;2.Y.157.154; 2.Y.157.157; 2.Y.157.166; 2.Y.157.169; 2.Y.157.172;2.Y.157.175; 2.Y.157.240; 2.Y.157.244; 2.Y.166.228; 2.Y.166.229;2.Y.166.230; 2.Y.166.231; 2.Y.166.236; 2.Y.166.237; 2.Y.166.238;2.Y.166.239; 2.Y.166.154; 2.Y.166.157; 2.Y.166.166; 2.Y.166.169;2.Y.166.172; 2.Y.166.175; 2.Y.166.240; 2.Y.166.244; 2.Y.169.228;2.Y.169.229; 2.Y.169.230; 2.Y.169.231; 2.Y.169.236; 2.Y.169.237;2.Y.169.238; 2.Y.169.239; 2.Y.169.154; 2.Y.169.157; 2.Y.169.166;2.Y.169.169; 2.Y.169.172; 2.Y.169.175; 2.Y.169.240; 2.Y.169.244;2.Y.172.228; 2.Y.172.229; 2.Y.172.230; 2.Y.172.231; 2.Y.172.236;2.Y.172.237; 2.Y.172.238; 2.Y.172.239; 2.Y.172.154; 2.Y.172.157;2.Y.172.166; 2.Y.172.169; 2.Y.172.172; 2.Y.172.175; 2.Y.172.240;2.Y.172.244; 2.Y.175.228; 2.Y.175.229; 2.Y.175.230; 2.Y.175.231;2.Y.175.236; 2.Y.175.237; 2.Y.175.238; 2.Y.175.239; 2.Y.175.154;2.Y.175.157; 2.Y.175.166; 2.Y.175.169; 2.Y.175.172; 2.Y.175.175;2.Y.175.240; 2.Y.175.244; 2.Y.240.228; 2.Y.240.229; 2.Y.240.230;2.Y.240.231; 2.Y.240.236; 2.Y.240.237; 2.Y.240.238; 2.Y.240.239;2.Y.240.154; 2.Y.240.157; 2.Y.240.166; 2.Y.240.169; 2.Y.240.172;2.Y.240.175; 2.Y.240.240; 2.Y.240.244; 2.Y.244.228; 2.Y.244.229;2.Y.244.230; 2.Y.244.231; 2.Y.244.236; 2.Y.244.237; 2.Y.244.238;2.Y.244.239; 2.Y.244.154; 2.Y.244.157; 2.Y.244.166; 2.Y.244.169;2.Y.244.172; 2.Y.244.175; 2.Y.244.240; 2.Y.244.244; Prodrugs of 3.B3.B.228.228; 3.B.228.229; 3.B.228.230; 3.B.228.231; 3.B.228.236;3.B.228.237; 3.B.228.238; 3.B.228.239; 3.B.228.154; 3.B.228.157;3.B.228.166; 3.B.228.169; 3.B.228.172; 3.B.228.175; 3.B.228.240;3.B.228.244; 3.B.229.228; 3.B.229.229; 3.B.229.230; 3.B.229.231;3.B.229.236; 3.B.229.237; 3.B.229.238; 3.B.229.239; 3.B.229.154;3.B.229.157; 3.B.229.166; 3.B.229.169; 3.B.229.172; 3.B.229.175;3.B.229.240; 3.B.229.244; 3.B.230.228; 3.B.230.229; 3.B.230.230;3.B.230.231; 3.B.230.236; 3.B.230.237; 3.B.230.238; 3.B.230.239;3.B.230.154; 3.B.230.157; 3.B.230.166; 3.B.230.169; 3.B.230.172;3.B.230.175; 3.B.230.240; 3.B.230.244; 3.B.231.228; 3.B.231.229;3.B.231.230; 3.B.231.231; 3.B.231.236; 3.B.231.237; 3.B.231.238;3.B.231.239; 3.B.231.154; 3.B.231.157; 3.B.231.166; 3.B.231.169;3.B.231.172; 3.B.231.175; 3.B.231.240; 3.B.231.244; 3.B.236.228;3.B.236.229; 3.B.236.230; 3.B.236.231; 3.B.236.236; 3.B.236.237;3.B.236.238; 3.B.236.239; 3.B.236.154; 3.B.236.157; 3.B.236.166;3.B.236.169; 3.B.236.172; 3.B.236.175; 3.B.236.240; 3.B.236.244;3.B.237.228; 3.B.237.229; 3.B.237.230; 3.B.237.231; 3.B.237.236;3.B.237.237; 3.B.237.238; 3.B.237.239; 3.B.237.154; 3.B.237.157;3.B.237.166; 3.B.237.169; 3.B.237.172; 3.B.237.175; 3.B.237.240;3.B.237.244; 3.B.238.228; 3.B.238.229; 3.B.238.230; 3.B.238.231;3.B.238.236; 3.B.238.237; 3.B.238.238; 3.B.238.239; 3.B.238.154;3.B.238.157; 3.B.238.166; 3.B.238.169; 3.B.238.172; 3.B.238.175;3.B.238.240; 3.B.238.244; 3.B.239.228; 3.B.239.229; 3.B.239.230;3.B.239.231; 3.B.239.236; 3.B.239.237; 3.B.239.238; 3.B.239.239;3.B.239.154; 3.B.239.157; 3.B.239.166; 3.B.239.169; 3.B.239.172;3.B.239.175; 3.B.239.240; 3.B.239.244; 3.B.154.228; 3.B.154.229;3.B.154.230; 3.B.154.231; 3.B.154.236; 3.B.154.237; 3.B.154.238;3.B.154.239; 3.B.154.154; 3.B.154.157; 3.B.154.166; 3.B.154.169;3.B.154.172; 3.B.154.175; 3.B.154.240; 3.B.154.244; 3.B.157.228;3.B.157.229; 3.B.157.230; 3.B.157.231; 3.B.157.236; 3.B.157.237;3.B.157.238; 3.B.157.239; 3.B.157.154; 3.B.157.157; 3.B.157.166;3.B.157.169; 3.B.157.172; 3.B.157.175; 3.B.157.240; 3.B.157.244;3.B.166.228; 3.B.166.229; 3.B.166.230; 3.B.166.231; 3.B.166.236;3.B.166.237; 3.B.166.238; 3.B.166.239; 3.B.166.154; 3.B.166.157;3.B.166.166; 3.B.166.169; 3.B.166.172; 3.B.166.175; 3.B.166.240;3.B.166.244; 3.B.169.228; 3.B.169.229; 3.B.169.230; 3.B.169.231;3.B.169.236; 3.B.169.237; 3.B.169.238; 3.B.169.239; 3.B.169.154;3.B.169.157; 3.B.169.166; 3.B.169.169; 3.B.169.172; 3.B.169.175;3.B.169.240; 3.B.169.244; 3.B.172.228; 3.B.172.229; 3.B.172.230;3.B.172.231; 3.B.172.236; 3.B.172.237; 3.B.172.238; 3.B.172.239;3.B.172.154; 3.B.172.157; 3.B.172.166; 3.B.172.169; 3.B.172.172;3.B.172.175; 3.B.172.240; 3.B.172.244; 3.B.175.228; 3.B.175.229;3.B.175.230; 3.B.175.231; 3.B.175.236; 3.B.175.237; 3.B.175.238;3.B.175.239; 3.B.175.154; 3.B.175.157; 3.B.175.166; 3.B.175.169;3.B.175.172; 3.B.175.175; 3.B.175.240; 3.B.175.244; 3.B.240.228;3.B.240.229; 3.B.240.230; 3.B.240.231; 3.B.240.236; 3.B.240.237;3.B.240.238; 3.B.240.239; 3.B.240.154; 3.B.240.157; 3.B.240.166;3.B.240.169; 3.B.240.172; 3.B.240.175; 3.B.240.240; 3.B.240.244;3.B.244.228; 3.B.244.229; 3.B.244.230; 3.B.244.231; 3.B.244.236;3.B.244.237; 3.B.244.238; 3.B.244.239; 3.B.244.154; 3.B.244.157;3.B.244.166; 3.B.244.169; 3.B.244.172; 3.B.244.175; 3.B.244.240;3.B.244.244; Prodrugs of 3.D 3.D.228.228; 3.D.228.229; 3.D.228.230;3.D.228.231; 3.D.228.236; 3.D.228.237; 3.D.228.238; 3.D.228.239;3.D.228.154; 3.D.228.157; 3.D.228.166; 3.D.228.169; 3.D.228.172;3.D.228.175; 3.D.228.240; 3.D.228.244; 3.D.229.228; 3.D.229.229;3.D.229.230; 3.D.229.231; 3.D.229.236; 3.D.229.237; 3.D.229.238;3.D.229.239; 3.D.229.154; 3.D.229.157; 3.D.229.166; 3.D.229.169;3.D.229.172; 3.D.229.175; 3.D.229.240; 3.D.229.244; 3.D.230.228;3.D.230.229; 3.D.230.230; 3.D.230.231; 3.D.230.236; 3.D.230.237;3.D.230.238; 3.D.230.239; 3.D.230.154; 3.D.230.157; 3.D.230.166;3.D.230.169; 3.D.230.172; 3.D.230.175; 3.D.230.240; 3.D.230.244;3.D.231.228; 3.D.231.229; 3.D.231.230; 3.D.231.231; 3.D.231.236;3.D.231.237; 3.D.231.238; 3.D.231.239; 3.D.231.154; 3.D.231.157;3.D.231.166; 3.D.231.169; 3.D.231.172; 3.D.231.175; 3.D.231.240;3.D.231.244; 3.D.236.228; 3.D.236.229; 3.D.236.230; 3.D.236.231;3.D.236.236; 3.D.236.237; 3.D.236.238; 3.D.236.239; 3.D.236.154;3.D.236.157; 3.D.236.166; 3.D.236.169; 3.D.236.172; 3.D.236.175;3.D.236.240; 3.D.236.244; 3.D.237.228; 3.D.237.229; 3.D.237.230;3.D.237.231; 3.D.237.236; 3.D.237.237; 3.D.237.238; 3.D.237.239;3.D.237.154; 3.D.237.157; 3.D.237.166; 3.D.237.169; 3.D.237.172;3.D.237.175; 3.D.237.240; 3.D.237.244; 3.D.238.228; 3.D.238.229;3.D.238.230; 3.D.238.231; 3.D.238.236; 3.D.238.237; 3.D.238.238;3.D.238.239; 3.D.238.154; 3.D.238.157; 3.D.238.166; 3.D.238.169;3.D.238.172; 3.D.238.175; 3.D.238.240; 3.D.238.244; 3.D.239.228;3.D.239.229; 3.D.239.230; 3.D.239.231; 3.D.239.236; 3.D.239.237;3.D.239.238; 3.D.239.239; 3.D.239.154; 3.D.239.157; 3.D.239.166;3.D.239.169; 3.D.239.172; 3.D.239.175; 3.D.239.240; 3.D.239.244;3.D.154.228; 3.D.154.229; 3.D.154.230; 3.D.154.231; 3.D.154.236;3.D.154.237; 3.D.154.238; 3.D.154.239; 3.D.154.154; 3.D.154.157;3.D.154.166; 3.D.154.169; 3.D.154.172; 3.D.154.175; 3.D.154.240;3.D.154.244; 3.D.157.228; 3.D.157.229; 3.D.157.230; 3.D.157.231;3.D.157.236; 3.D.157.237; 3.D.157.238; 3.D.157.239; 3.D.157.154;3.D.157.157; 3.D.157.166; 3.D.157.169; 3.D.157.172; 3.D.157.175;3.D.157.240; 3.D.157.244; 3.D.166.228; 3.D.166.229; 3.D.166.230;3.D.166.231; 3.D.166.236; 3.D.166.237; 3.D.166.238; 3.D.166.239;3.D.166.154; 3.D.166.157; 3.D.166.166; 3.D.166.169; 3.D.166.172;3.D.166.175; 3.D.166.240; 3.D.166.244; 3.D.169.228; 3.D.169.229;3.D.169.230; 3.D.169.231; 3.D.169.236; 3.D.169.237; 3.D.169.238;3.D.169.239; 3.D.169.154; 3.D.169.157; 3.D.169.166; 3.D.169.169;3.D.169.172; 3.D.169.175; 3.D.169.240; 3.D.169.244; 3.D.172.228;3.D.172.229; 3.D.172.230; 3.D.172.231; 3.D.172.236; 3.D.172.237;3.D.172.238; 3.D.172.239; 3.D.172.154; 3.D.172.157; 3.D.172.166;3.D.172.169; 3.D.172.172; 3.D.172.175; 3.D.172.240; 3.D.172.244;3.D.175.228; 3.D.175.229; 3.D.175.230; 3.D.175.231; 3.D.175.236;3.D.175.237; 3.D.175.238; 3.D.175.239; 3.D.175.154; 3.D.175.157;3.D.175.166; 3.D.175.169; 3.D.175.172; 3.D.175.175; 3.D.175.240;3.D.175.244; 3.D.240.228; 3.D.240.229; 3.D.240.230; 3.D.240.231;3.D.240.236; 3.D.240.237; 3.D.240.238; 3.D.240.239; 3.D.240.154;3.D.240.157; 3.D.240.166; 3.D.240.169; 3.D.240.172; 3.D.240.175;3.D.240.240; 3.D.240.244; 3.D.244.228; 3.D.244.229; 3.D.244.230;3.D.244.231; 3.D.244.236; 3.D.244.237; 3.D.244.238; 3.D.244.239;3.D.244.154; 3.D.244.157; 3.D.244.166; 3.D.244.169; 3.D.244.172;3.D.244.175; 3.D.244.240; 3.D.244.244; Prodrugs of 3.E 3.E.228.228;3.E.228.229; 3.E.228.230; 3.E.228.231; 3.E.228.236; 3.E.228.237;3.E.228.238; 3.E.228.239; 3.E.228.154; 3.E.228.157; 3.E.228.166;3.E.228.169; 3.E.228.172; 3.E.228.175; 3.E.228.240; 3.E.228.244;3.E.229.228; 3.E.229.229; 3.E.229.230; 3.E.229.231; 3.E.229.236;3.E.229.237; 3.E.229.238; 3.E.229.239; 3.E.229.154; 3.E.229.157;3.E.229.166; 3.E.229.169; 3.E.229.172; 3.E.229.175; 3.E.229.240;3.E.229.244; 3.E.230.228; 3.E.230.229; 3.E.230.230; 3.E.230.231;3.E.230.236; 3.E.230.237; 3.E.230.238; 3.E.230.239; 3.E.230.154;3.E.230.157; 3.E.230.166; 3.E.230.169; 3.E.230.172; 3.E.230.175;3.E.230.240; 3.E.230.244; 3.E.231.228; 3.E.231.229; 3.E.231.230;3.E.231.231; 3.E.231.236; 3.E.231.237; 3.E.231.238; 3.E.231.239;3.E.231.154; 3.E.231.157; 3.E.231.166; 3.E.231.169; 3.E.231.172;3.E.231.175; 3.E.231.240; 3.E.231.244; 3.E.236.228; 3.E.236.229;3.E.236.230; 3.E.236.231; 3.E.236.236; 3.E.236.237; 3.E.236.238;3.E.236.239; 3.E.236.154; 3.E.236.157; 3.E.236.166; 3.E.236.169;3.E.236.172; 3.E.236.175; 3.E.236.240; 3.E.236.244; 3.E.237.228;3.E.237.229; 3.E.237.230; 3.E.237.231; 3.E.237.236; 3.E.237.237;3.E.237.238; 3.E.237.239; 3.E.237.154; 3.E.237.157; 3.E.237.166;3.E.237.169; 3.E.237.172; 3.E.237.175; 3.E.237.240; 3.E.237.244;3.E.238.228; 3.E.238.229; 3.E.238.230; 3.E.238.231; 3.E.238.236;3.E.238.237; 3.E.238.238; 3.E.238.239; 3.E.238.154; 3.E.238.157;3.E.238.166; 3.E.238.169; 3.E.238.172; 3.E.238.175; 3.E.238.240;3.E.238.244; 3.E.239.228; 3.E.239.229; 3.E.239.230; 3.E.239.231;3.E.239.236; 3.E.239.237; 3.E.239.238; 3.E.239.239; 3.E.239.154;3.E.239.157; 3.E.239.166; 3.E.239.169; 3.E.239.172; 3.E.239.175;3.E.239.240; 3.E.239.244; 3.E.154.228; 3.E.154.229; 3.E.154.230;3.E.154.231; 3.E.154.236; 3.E.154.237; 3.E.154.238; 3.E.154.239;3.E.154.154; 3.E.154.157; 3.E.154.166; 3.E.154.169; 3.E.154.172;3.E.154.175; 3.E.154.240; 3.E.154.244; 3.E.157.228; 3.E.157.229;3.E.157.230; 3.E.157.231; 3.E.157.236; 3.E.157.237; 3.E.157.238;3.E.157.239; 3.E.157.154; 3.E.157.157; 3.E.157.166; 3.E.157.169;3.E.157.172; 3.E.157.175; 3.E.157.240; 3.E.157.244; 3.E.166.228;3.E.166.229; 3.E.166.230; 3.E.166.231; 3.E.166.236; 3.E.166.237;3.E.166.238; 3.E.166.239; 3.E.166.154; 3.E.166.157; 3.E.166.166;3.E.166.169; 3.E.166.172; 3.E.166.175; 3.E.166.240; 3.E.166.244;3.E.169.228; 3.E.169.229; 3.E.169.230; 3.E.169.231; 3.E.169.236;3.E.169.237; 3.E.169.238; 3.E.169.239; 3.E.169.154; 3.E.169.157;3.E.169.166; 3.E.169.169; 3.E.169.172; 3.E.169.175; 3.E.169.240;3.E.169.244; 3.E.172.228; 3.E.172.229; 3.E.172.230; 3.E.172.231;3.E.172.236; 3.E.172.237; 3.E.172.238; 3.E.172.239; 3.E.172.154;3.E.172.157; 3.E.172.166; 3.E.172.169; 3.E.172.172; 3.E.172.175;3.E.172.240; 3.E.172.244; 3.E.175.228; 3.E.175.229; 3.E.175.230;3.E.175.231; 3.E.175.236; 3.E.175.237; 3.E.175.238; 3.E.175.239;3.E.175.154; 3.E.175.157; 3.E.175.166; 3.E.175.169; 3.E.175.172;3.E.175.175; 3.E.175.240; 3.E.175.244; 3.E.240.228; 3.E.240.229;3.E.240.230; 3.E.240.231; 3.E.240.236; 3.E.240.237; 3.E.240.238;3.E.240.239; 3.E.240.154; 3.E.240.157; 3.E.240.166; 3.E.240.169;3.E.240.172; 3.E.240.175; 3.E.240.240; 3.E.240.244; 3.E.244.228;3.E.244.229; 3.E.244.230; 3.E.244.231; 3.E.244.236; 3.E.244.237;3.E.244.238; 3.E.244.239; 3.E.244.154; 3.E.244.157; 3.E.244.166;3.E.244.169; 3.E.244.172; 3.E.244.175; 3.E.244.240; 3.E.244.244;Prodrugs of 3.G 3.G.228.228; 3.G.228.229; 3.G.228.230; 3.G.228.231;3.G.228.236; 3.G.228.237; 3.G.228.238; 3.G.228.239; 3.G.228.154;3.G.228.157; 3.G.228.166; 3.G.228.169; 3.G.228.172; 3.G.228.175;3.G.228.240; 3.G.228.244; 3.G.229.228; 3.G.229.229; 3.G.229.230;3.G.229.231; 3.G.229.236; 3.G.229.237; 3.G.229.238; 3.G.229.239;3.G.229.154; 3.G.229.157; 3.G.229.166; 3.G.229.169; 3.G.229.172;3.G.229.175; 3.G.229.240; 3.G.229.244; 3.G.230.228; 3.G.230.229;3.G.230.230; 3.G.230.231; 3.G.230.236; 3.G.230.237; 3.G.230.238;3.G.230.239; 3.G.230.154; 3.G.230.157; 3.G.230.166; 3.G.230.169;3.G.230.172; 3.G.230.175; 3.G.230.240; 3.G.230.244; 3.G.231.228;3.G.231.229; 3.G.231.230; 3.G.231.231; 3.G.231.236; 3.G.231.237;3.G.231.238; 3.G.231.239; 3.G.231.154; 3.G.231.157; 3.G.231.166;3.G.231.169; 3.G.231.172; 3.G.231.175; 3.G.231.240; 3.G.231.244;3.G.236.228; 3.G.236.229; 3.G.236.230; 3.G.236.231; 3.G.236.236;3.G.236.237; 3.G.236.238; 3.G.236.239; 3.G.236.154; 3.G.236.157;3.G.236.166; 3.G.236.169; 3.G.236.172; 3.G.236.175; 3.G.236.240;3.G.236.244; 3.G.237.228; 3.G.237.229; 3.G.237.230; 3.G.237.231;3.G.237.236; 3.G.237.237; 3.G.237.238; 3.G.237.239; 3.G.237.154;3.G.237.157; 3.G.237.166; 3.G.237.169; 3.G.237.172; 3.G.237.175;3.G.237.240; 3.G.237.244; 3.G.238.228; 3.G.238.229; 3.G.238.230;3.G.238.231; 3.G.238.236; 3.G.238.237; 3.G.238.238; 3.G.238.239;3.G.238.154; 3.G.238.157; 3.G.238.166; 3.G.238.169; 3.G.238.172;3.G.238.175; 3.G.238.240; 3.G.238.244; 3.G.239.228; 3.G.239.229;3.G.239.230; 3.G.239.231; 3.G.239.236; 3.G.239.237; 3.G.239.238;3.G.239.239; 3.G.239.154; 3.G.239.157; 3.G.239.166; 3.G.239.169;3.G.239.172; 3.G.239.175; 3.G.239.240; 3.G.239.244; 3.G.154.228;3.G.154.229; 3.G.154.230; 3.G.154.231; 3.G.154.236; 3.G.154.237;3.G.154.238; 3.G.154.239; 3.G.154.154; 3.G.154.157; 3.G.154.166;3.G.154.169; 3.G.154.172; 3.G.154.175; 3.G.154.240; 3.G.154.244;3.G.157.228; 3.G.157.229; 3.G.157.230; 3.G.157.231; 3.G.157.236;3.G.157.237; 3.G.157.238; 3.G.157.239; 3.G.157.154; 3.G.157.157;3.G.157.166; 3.G.157.169; 3.G.157.172; 3.G.157.175; 3.G.157.240;3.G.157.244; 3.G.166.228; 3.G.166.229; 3.G.166.230; 3.G.166.231;3.G.166.236; 3.G.166.237; 3.G.166.238; 3.G.166.239; 3.G.166.154;3.G.166.157; 3.G.166.166; 3.G.166.169; 3.G.166.172; 3.G.166.175;3.G.166.240; 3.G.166.244; 3.G.169.228; 3.G.169.229; 3.G.169.230;3.G.169.231; 3.G.169.236; 3.G.169.237; 3.G.169.238; 3.G.169.239;3.G.169.154; 3.G.169.157; 3.G.169.166; 3.G.169.169; 3.G.169.172;3.G.169.175; 3.G.169.240; 3.G.169.244; 3.G.172.228; 3.G.172.229;3.G.172.230; 3.G.172.231; 3.G.172.236; 3.G.172.237; 3.G.172.238;3.G.172.239; 3.G.172.154; 3.G.172.157; 3.G.172.166; 3.G.172.169;3.G.172.172; 3.G.172.175; 3.G.172.240; 3.G.172.244; 3.G.175.228;3.G.175.229; 3.G.175.230; 3.G.175.231; 3.G.175.236; 3.G.175.237;3.G.175.238; 3.G.175.239; 3.G.175.154; 3.G.175.157; 3.G.175.166;3.G.175.169; 3.G.175.172; 3.G.175.175; 3.G.175.240; 3.G.175.244;3.G.240.228; 3.G.240.229; 3.G.240.230; 3.G.240.231; 3.G.240.236;3.G.240.237; 3.G.240.238; 3.G.240.239; 3.G.240.154; 3.G.240.157;3.G.240.166; 3.G.240.169; 3.G.240.172; 3.G.240.175; 3.G.240.240;3.G.240.244; 3.G.244.228; 3.G.244.229; 3.G.244.230; 3.G.244.231;3.G.244.236; 3.G.244.237; 3.G.244.238; 3.G.244.239; 3.G.244.154;3.G.244.157; 3.G.244.166; 3.G.244.169; 3.G.244.172; 3.G.244.175;3.G.244.240; 3.G.244.244; Prodrugs of 3.I 3.I.228.228; 3.I.228.229;3.I.228.230; 3.I.228.231; 3.I.228.236; 3.I.228.237; 3.I.228.238;3.I.228.239; 3.I.228.154; 3.I.228.157; 3.I.228.166; 3.I.228.169;3.I.228.172; 3.I.228.175; 3.I.228.240; 3.I.228.244; 3.I.229.228;3.I.229.229; 3.I.229.230; 3.I.229.231; 3.I.229.236; 3.I.229.237;3.I.229.238; 3.I.229.239; 3.I.229.154; 3.I.229.157; 3.I.229.166;3.I.229.169; 3.I.229.172; 3.I.229.175; 3.I.229.240; 3.I.229.244;3.I.230.228; 3.I.230.229; 3.I.230.230; 3.I.230.231; 3.I.230.236;3.I.230.237; 3.I.230.238; 3.I.230.239; 3.I.230.154; 3.I.230.157;3.I.230.166; 3.I.230.169; 3.I.230.172; 3.I.230.175; 3.I.230.240;3.I.230.244; 3.I.231.228; 3.I.231.229; 3.I.231.230; 3.I.231.231;3.I.231.236; 3.I.231.237; 3.I.231.238; 3.I.231.239; 3.I.231.154;3.I.231.157; 3.I.231.166; 3.I.231.169; 3.I.231.172; 3.I.231.175;3.I.231.240; 3.I.231.244; 3.I.236.228; 3.I.236.229; 3.I.236.230;3.I.236.231; 3.I.236.236; 3.I.236.237; 3.I.236.238; 3.I.236.239;3.I.236.154; 3.I.236.157; 3.I.236.166; 3.I.236.169; 3.I.236.172;3.I.236.175; 3.I.236.240; 3.I.236.244; 3.I.237.228; 3.I.237.229;3.I.237.230; 3.I.237.231; 3.I.237.236; 3.I.237.237; 3.I.237.238;3.I.237.239; 3.I.237.154; 3.I.237.157; 3.I.237.166; 3.I.237.169;3.I.237.172; 3.I.237.175; 3.I.237.240; 3.I.237.244; 3.I.238.228;3.I.238.229; 3.I.238.230; 3.I.238.231; 3.I.238.236; 3.I.238.237;3.I.238.238; 3.I.238.239; 3.I.238.154; 3.I.238.157; 3.I.238.166;3.I.238.169; 3.I.238.172; 3.I.238.175; 3.I.238.240; 3.I.238.244;3.I.239.228; 3.I.239.229; 3.I.239.230; 3.I.239.231; 3.I.239.236;3.I.239.237; 3.I.239.238; 3.I.239.239; 3.I.239.154; 3.I.239.157;3.I.239.166; 3.I.239.169; 3.I.239.172; 3.I.239.175; 3.I.239.240;3.I.239.244; 3.I.154.228; 3.I.154.229; 3.I.154.230; 3.I.154.231;3.I.154.236; 3.I.154.237; 3.I.154.238; 3.I.154.239; 3.I.154.154;3.I.154.157; 3.I.154.166; 3.I.154.169; 3.I.154.172; 3.I.154.175;3.I.154.240; 3.I.154.244; 3.I.157.228; 3.I.157.229; 3.I.157.230;3.I.157.231; 3.I.157.236; 3.I.157.237; 3.I.157.238; 3.I.157.239;3.I.157.154; 3.I.157.157; 3.I.157.166; 3.I.157.169; 3.I.157.172;3.I.157.175; 3.I.157.240; 3.I.157.244; 3.I.166.228; 3.I.166.229;3.I.166.230; 3.I.166.231; 3.I.166.236; 3.I.166.237; 3.I.166.238;3.I.166.239; 3.I.166.154; 3.I.166.157; 3.I.166.166; 3.I.166.169;3.I.166.172; 3.I.166.175; 3.I.166.240; 3.I.166.244; 3.I.169.228;3.I.169.229; 3.I.169.230; 3.I.169.231; 3.I.169.236; 3.I.169.237;3.I.169.238; 3.I.169.239; 3.I.169.154; 3.I.169.157; 3.I.169.166;3.I.169.169; 3.I.169.172; 3.I.169.175; 3.I.169.240; 3.I.169.244;3.I.172.228; 3.I.172.229; 3.I.172.230; 3.I.172.231; 3.I.172.236;3.I.172.237; 3.I.172.238; 3.I.172.239; 3.I.172.154; 3.I.172.157;3.I.172.166; 3.I.172.169; 3.I.172.172; 3.I.172.175; 3.I.172.240;3.I.172.244; 3.I.175.228; 3.I.175.229; 3.I.175.230; 3.I.175.231;3.I.175.236; 3.I.175.237; 3.I.175.238; 3.I.175.239; 3.I.175.154;3.I.175.157; 3.I.175.166; 3.I.175.169; 3.I.175.172; 3.I.175.175;3.I.175.240; 3.I.175.244; 3.I.240.228; 3.I.240.229; 3.I.240.230;3.I.240.231; 3.I.240.236; 3.I.240.237; 3.I.240.238; 3.I.240.239;3.I.240.154; 3.I.240.157; 3.I.240.166; 3.I.240.169; 3.I.240.172;3.I.240.175; 3.I.240.240; 3.I.240.244; 3.I.244.228; 3.I.244.229;3.I.244.230; 3.I.244.231; 3.I.244.236; 3.I.244.237; 3.I.244.238;3.I.244.239; 3.I.244.154; 3.I.244.157; 3.I.244.166; 3.I.244.169;3.I.244.172; 3.I.244.175; 3.I.244.240; 3.I.244.244; Prodrugs of 3.J3.J.228.228; 3.J.228.229; 3.J.228.230; 3.J.228.231; 3.J.228.236;3.J.228.237; 3.J.228.238; 3.J.228.239; 3.J.228.154; 3.J.228.157;3.J.228.166; 3.J.228.169; 3.J.228.172; 3.J.228.175; 3.J.228.240;3.J.228.244; 3.J.229.228; 3.J.229.229; 3.J.229.230; 3.J.229.231;3.J.229.236; 3.J.229.237; 3.J.229.238; 3.J.229.239; 3.J.229.154;3.J.229.157; 3.J.229.166; 3.J.229.169; 3.J.229.172; 3.J.229.175;3.J.229.240; 3.J.229.244; 3.J.230.228; 3.J.230.229; 3.J.230.230;3.J.230.231; 3.J.230.236; 3.J.230.237; 3.J.230.238; 3.J.230.239;3.J.230.154; 3.J.230.157; 3.J.230.166; 3.J.230.169; 3.J.230.172;3.J.230.175; 3.J.230.240; 3.J.230.244; 3.J.231.228; 3.J.231.229;3.J.231.230; 3.J.231.231; 3.J.231.236; 3.J.231.237; 3.J.231.238;3.J.231.239; 3.J.231.154; 3.J.231.157; 3.J.231.166; 3.J.231.169;3.J.231.172; 3.J.231.175; 3.J.231.240; 3.J.231.244; 3.J.236.228;3.J.236.229; 3.J.236.230; 3.J.236.231; 3.J.236.236; 3.J.236.237;3.J.236.238; 3.J.236.239; 3.J.236.154; 3.J.236.157; 3.J.236.166;3.J.236.169; 3.J.236.172; 3.J.236.175; 3.J.236.240; 3.J.236.244;3.J.237.228; 3.J.237.229; 3.J.237.230; 3.J.237.231; 3.J.237.236;3.J.237.237; 3.J.237.238; 3.J.237.239; 3.J.237.154; 3.J.237.157;3.J.237.166; 3.J.237.169; 3.J.237.172; 3.J.237.175; 3.J.237.240;3.J.237.244; 3.J.238.228; 3.J.238.229; 3.J.238.230; 3.J.238.231;3.J.238.236; 3.J.238.237; 3.J.238.238; 3.J.238.239; 3.J.238.154;3.J.238.157; 3.J.238.166; 3.J.238.169; 3.J.238.172; 3.J.238.175;3.J.238.240; 3.J.238.244; 3.J.239.228; 3.J.239.229; 3.J.239.230;3.J.239.231; 3.J.239.236; 3.J.239.237; 3.J.239.238; 3.J.239.239;3.J.239.154; 3.J.239.157; 3.J.239.166; 3.J.239.169; 3.J.239.172;3.J.239.175; 3.J.239.240; 3.J.239.244; 3.J.154.228; 3.J.154.229;3.J.154.230; 3.J.154.231; 3.J.154.236; 3.J.154.237; 3.J.154.238;3.J.154.239; 3.J.154.154; 3.J.154.157; 3.J.154.166; 3.J.154.169;3.J.154.172; 3.J.154.175; 3.J.154.240; 3.J.154.244; 3.J.157.228;3.J.157.229; 3.J.157.230; 3.J.157.231; 3.J.157.236; 3.J.157.237;3.J.157.238; 3.J.157.239; 3.J.157.154; 3.J.157.157; 3.J.157.166;3.J.157.169; 3.J.157.172; 3.J.157.175; 3.J.157.240; 3.J.157.244;3.J.166.228; 3.J.166.229; 3.J.166.230; 3.J.166.231; 3.J.166.236;3.J.166.237; 3.J.166.238; 3.J.166.239; 3.J.166.154; 3.J.166.157;3.J.166.166; 3.J.166.169; 3.J.166.172; 3.J.166.175; 3.J.166.240;3.J.166.244; 3.J.169.228; 3.J.169.229; 3.J.169.230; 3.J.169.231;3.J.169.236; 3.J.169.237; 3.J.169.238; 3.J.169.239; 3.J.169.154;3.J.169.157; 3.J.169.166; 3.J.169.169; 3.J.169.172; 3.J.169.175;3.J.169.240; 3.J.169.244; 3.J.172.228; 3.J.172.229; 3.J.172.230;3.J.172.231; 3.J.172.236; 3.J.172.237; 3.J.172.238; 3.J.172.239;3.J.172.154; 3.J.172.157; 3.J.172.166; 3.J.172.169; 3.J.172.172;3.J.172.175; 3.J.172.240; 3.J.172.244; 3.J.175.228; 3.J.175.229;3.J.175.230; 3.J.175.231; 3.J.175.236; 3.J.175.237; 3.J.175.238;3.J.175.239; 3.J.175.154; 3.J.175.157; 3.J.175.166; 3.J.175.169;3.J.175.172; 3.J.175.175; 3.J.175.240; 3.J.175.244; 3.J.240.228;3.J.240.229; 3.J.240.230; 3.J.240.231; 3.J.240.236; 3.J.240.237;3.J.240.238; 3.J.240.239; 3.J.240.154; 3.J.240.157; 3.J.240.166;3.J.240.169; 3.J.240.172; 3.J.240.175; 3.J.240.240; 3.J.240.244;3.J.244.228; 3.J.244.229; 3.J.244.230; 3.J.244.231; 3.J.244.236;3.J.244.237; 3.J.244.238; 3.J.244.239; 3.J.244.154; 3.J.244.157;3.J.244.166; 3.J.244.169; 3.J.244.172; 3.J.244.175; 3.J.244.240;3.J.244.244; Prodrugs of 3.L 3.L.228.228; 3.L.228.229; 3.L.228.230;3.L.228.231; 3.L.228.236; 3.L.228.237; 3.L.228.238; 3.L.228.239;3.L.228.154; 3.L.228.157; 3.L.228.166; 3.L.228.169; 3.L.228.172;3.L.228.175; 3.L.228.240; 3.L.228.244; 3.L.229.228; 3.L.229.229;3.L.229.230; 3.L.229.231; 3.L.229.236; 3.L.229.237; 3.L.229.238;3.L.229.239; 3.L.229.154; 3.L.229.157; 3.L.229.166; 3.L.229.169;3.L.229.172; 3.L.229.175; 3.L.229.240; 3.L.229.244; 3.L.230.228;3.L.230.229; 3.L.230.230; 3.L.230.231; 3.L.230.236; 3.L.230.237;3.L.230.238; 3.L.230.239; 3.L.230.154; 3.L.230.157; 3.L.230.166;3.L.230.169; 3.L.230.172; 3.L.230.175; 3.L.230.240; 3.L.230.244;3.L.231.228; 3.L.231.229; 3.L.231.230; 3.L.231.231; 3.L.231.236;3.L.231.237; 3.L.231.238; 3.L.231.239; 3.L.231.154; 3.L.231.157;3.L.231.166; 3.L.231.169; 3.L.231.172; 3.L.231.175; 3.L.231.240;3.L.231.244; 3.L.236.228; 3.L.236.229; 3.L.236.230; 3.L.236.231;3.L.236.236; 3.L.236.237; 3.L.236.238; 3.L.236.239; 3.L.236.154;3.L.236.157; 3.L.236.166; 3.L.236.169; 3.L.236.172; 3.L.236.175;3.L.236.240; 3.L.236.244; 3.L.237.228; 3.L.237.229; 3.L.237.230;3.L.237.231; 3.L.237.236; 3.L.237.237; 3.L.237.238; 3.L.237.239;3.L.237.154; 3.L.237.157; 3.L.237.166; 3.L.237.169; 3.L.237.172;3.L.237.175; 3.L.237.240; 3.L.237.244; 3.L.238.228; 3.L.238.229;3.L.238.230; 3.L.238.231; 3.L.238.236; 3.L.238.237; 3.L.238.238;3.L.238.239; 3.L.238.154; 3.L.238.157; 3.L.238.166; 3.L.238.169;3.L.238.172; 3.L.238.175; 3.L.238.240; 3.L.238.244; 3.L.239.228;3.L.239.229; 3.L.239.230; 3.L.239.231; 3.L.239.236; 3.L.239.237;3.L.239.238; 3.L.239.239; 3.L.239.154; 3.L.239.157; 3.L.239.166;3.L.239.169; 3.L.239.172; 3.L.239.175; 3.L.239.240; 3.L.239.244;3.L.154.228; 3.L.154.229; 3.L.154.230; 3.L.154.231; 3.L.154.236;3.L.154.237; 3.L.154.238; 3.L.154.239; 3.L.154.154; 3.L.154.157;3.L.154.166; 3.L.154.169; 3.L.154.172; 3.L.154.175; 3.L.154.240;3.L.154.244; 3.L.157.228; 3.L.157.229; 3.L.157.230; 3.L.157.231;3.L.157.236; 3.L.157.237; 3.L.157.238; 3.L.157.239; 3.L.157.154;3.L.157.157; 3.L.157.166; 3.L.157.169; 3.L.157.172; 3.L.157.175;3.L.157.240; 3.L.157.244; 3.L.166.228; 3.L.166.229; 3.L.166.230;3.L.166.231; 3.L.166.236; 3.L.166.237; 3.L.166.238; 3.L.166.239;3.L.166.154; 3.L.166.157; 3.L.166.166; 3.L.166.169; 3.L.166.172;3.L.166.175; 3.L.166.240; 3.L.166.244; 3.L.169.228; 3.L.169.229;3.L.169.230; 3.L.169.231; 3.L.169.236; 3.L.169.237; 3.L.169.238;3.L.169.239; 3.L.169.154; 3.L.169.157; 3.L.169.166; 3.L.169.169;3.L.169.172; 3.L.169.175; 3.L.169.240; 3.L.169.244; 3.L.172.228;3.L.172.229; 3.L.172.230; 3.L.172.231; 3.L.172.236; 3.L.172.237;3.L.172.238; 3.L.172.239; 3.L.172.154; 3.L.172.157; 3.L.172.166;3.L.172.169; 3.L.172.172; 3.L.172.175; 3.L.172.240; 3.L.172.244;3.L.175.228; 3.L.175.229; 3.L.175.230; 3.L.175.231; 3.L.175.236;3.L.175.237; 3.L.175.238; 3.L.175.239; 3.L.175.154; 3.L.175.157;3.L.175.166; 3.L.175.169; 3.L.175.172; 3.L.175.175; 3.L.175.240;3.L.175.244; 3.L.240.228; 3.L.240.229; 3.L.240.230; 3.L.240.231;3.L.240.236; 3.L.240.237; 3.L.240.238; 3.L.240.239; 3.L.240.154;3.L.240.157; 3.L.240.166; 3.L.240.169; 3.L.240.172; 3.L.240.175;3.L.240.240; 3.L.240.244; 3.L.244.228; 3.L.244.229; 3.L.244.230;3.L.244.231; 3.L.244.236; 3.L.244.237; 3.L.244.238; 3.L.244.239;3.L.244.154; 3.L.244.157; 3.L.244.166; 3.L.244.169; 3.L.244.172;3.L.244.175; 3.L.244.240; 3.L.244.244; Prodrugs of 3.O 3.O.228.228;3.O.228.229; 3.O.228.230; 3.O.228.231; 3.O.228.236; 3.O.228.237;3.O.228.238; 3.O.228.239; 3.O.228.154; 3.O.228.157; 3.O.228.166;3.O.228.169; 3.O.228.172; 3.O.228.175; 3.O.228.240; 3.O.228.244;3.O.229.228; 3.O.229.229; 3.O.229.230; 3.O.229.231; 3.O.229.236;3.O.229.237; 3.O.229.238; 3.O.229.239; 3.O.229.154; 3.O.229.157;3.O.229.166; 3.O.229.169; 3.O.229.172; 3.O.229.175; 3.O.229.240;3.O.229.244; 3.O.230.228; 3.O.230.229; 3.O.230.230; 3.O.230.231;3.O.230.236; 3.O.230.237; 3.O.230.238; 3.O.230.239; 3.O.230.154;3.O.230.157; 3.O.230.166; 3.O.230.169; 3.O.230.172; 3.O.230.175;3.O.230.240; 3.O.230.244; 3.O.231.228; 3.O.231.229; 3.O.231.230;3.O.231.231; 3.O.231.236; 3.O.231.237; 3.O.231.238; 3.O.231.239;3.O.231.154; 3.O.231.157; 3.O.231.166; 3.O.231.169; 3.O.231.172;3.O.231.175; 3.O.231.240; 3.O.231.244; 3.O.236.228; 3.O.236.229;3.O.236.230; 3.O.236.231; 3.O.236.236; 3.O.236.237; 3.O.236.238;3.O.236.239; 3.O.236.154; 3.O.236.157; 3.O.236.166; 3.O.236.169;3.O.236.172; 3.O.236.175; 3.O.236.240; 3.O.236.244; 3.O.237.228;3.O.237.229; 3.O.237.230; 3.O.237.231; 3.O.237.236; 3.O.237.237;3.O.237.238; 3.O.237.239; 3.O.237.154; 3.O.237.157; 3.O.237.166;3.O.237.169; 3.O.237.172; 3.O.237.175; 3.O.237.240; 3.O.237.244;3.O.238.228; 3.O.238.229; 3.O.238.230; 3.O.238.231; 3.O.238.236;3.O.238.237; 3.O.238.238; 3.O.238.239; 3.O.238.154; 3.O.238.157;3.O.238.166; 3.O.238.169; 3.O.238.172; 3.O.238.175; 3.O.238.240;3.O.238.244; 3.O.239.228; 3.O.239.229; 3.O.239.230; 3.O.239.231;3.O.239.236; 3.O.239.237; 3.O.239.238; 3.O.239.239; 3.O.239.154;3.O.239.157; 3.O.239.166; 3.O.239.169; 3.O.239.172; 3.O.239.175;3.O.239.240; 3.O.239.244; 3.O.154.228; 3.O.154.229; 3.O.154.230;3.O.154.231; 3.O.154.236; 3.O.154.237; 3.O.154.238; 3.O.154.239;3.O.154.154; 3.O.154.157; 3.O.154.166; 3.O.154.169; 3.O.154.172;3.O.154.175; 3.O.154.240; 3.O.154.244; 3.O.157.228; 3.O.157.229;3.O.157.230; 3.O.157.231; 3.O.157.236; 3.O.157.237; 3.O.157.238;3.O.157.239; 3.O.157.154; 3.O.157.157; 3.O.157.166; 3.O.157.169;3.O.157.172; 3.O.157.175; 3.O.157.240; 3.O.157.244; 3.O.166.228;3.O.166.229; 3.O.166.230; 3.O.166.231; 3.O.166.236; 3.O.166.237;3.O.166.238; 3.O.166.239; 3.O.166.154; 3.O.166.157; 3.O.166.166;3.O.166.169; 3.O.166.172; 3.O.166.175; 3.O.166.240; 3.O.166.244;3.O.169.228; 3.O.169.229; 3.O.169.230; 3.O.169.231; 3.O.169.236;3.O.169.237; 3.O.169.238; 3.O.169.239; 3.O.169.154; 3.O.169.157;3.O.169.166; 3.O.169.169; 3.O.169.172; 3.O.169.175; 3.O.169.240;3.O.169.244; 3.O.172.228; 3.O.172.229; 3.O.172.230; 3.O.172.231;3.O.172.236; 3.O.172.237; 3.O.172.238; 3.O.172.239; 3.O.172.154;3.O.172.157; 3.O.172.166; 3.O.172.169; 3.O.172.172; 3.O.172.175;3.O.172.240; 3.O.172.244; 3.O.175.228; 3.O.175.229; 3.O.175.230;3.O.175.231; 3.O.175.236; 3.O.175.237; 3.O.175.238; 3.O.175.239;3.O.175.154; 3.O.175.157; 3.O.175.166; 3.O.175.169; 3.O.175.172;3.O.175.175; 3.O.175.240; 3.O.175.244; 3.O.240.228; 3.O.240.229;3.O.240.230; 3.O.240.231; 3.O.240.236; 3.O.240.237; 3.O.240.238;3.O.240.239; 3.O.240.154; 3.O.240.157; 3.O.240.166; 3.O.240.169;3.O.240.172; 3.O.240.175; 3.O.240.240; 3.O.240.244; 3.O.244.228;3.O.244.229; 3.O.244.230; 3.O.244.231; 3.O.244.236; 3.O.244.237;3.O.244.238; 3.O.244.239; 3.O.244.154; 3.O.244.157; 3.O.244.166;3.O.244.169; 3.O.244.172; 3.O.244.175; 3.O.244.240; 3.O.244.244;Prodrugs of 3.P 3.P.228.228; 3.P.228.229; 3.P.228.230; 3.P.228.231;3.P.228.236; 3.P.228.237; 3.P.228.238; 3.P.228.239; 3.P.228.154;3.P.228.157; 3.P.228.166; 3.P.228.169; 3.P.228.172; 3.P.228.175;3.P.228.240; 3.P.228.244; 3.P.229.228; 3.P.229.229; 3.P.229.230;3.P.229.231; 3.P.229.236; 3.P.229.237; 3.P.229.238; 3.P.229.239;3.P.229.154; 3.P.229.157; 3.P.229.166; 3.P.229.169; 3.P.229.172;3.P.229.175; 3.P.229.240; 3.P.229.244; 3.P.230.228; 3.P.230.229;3.P.230.230; 3.P.230.231; 3.P.230.236; 3.P.230.237; 3.P.230.238;3.P.230.239; 3.P.230.154; 3.P.230.157; 3.P.230.166; 3.P.230.169;3.P.230.172; 3.P.230.175; 3.P.230.240; 3.P.230.244; 3.P.231.228;3.P.231.229; 3.P.231.230; 3.P.231.231; 3.P.231.236; 3.P.231.237;3.P.231.238; 3.P.231.239; 3.P.231.154; 3.P.231.157; 3.P.231.166;3.P.231.169; 3.P.231.172; 3.P.231.175; 3.P.231.240; 3.P.231.244;3.P.236.228; 3.P.236.229; 3.P.236.230; 3.P.236.231; 3.P.236.236;3.P.236.237; 3.P.236.238; 3.P.236.239; 3.P.236.154; 3.P.236.157;3.P.236.166; 3.P.236.169; 3.P.236.172; 3.P.236.175; 3.P.236.240;3.P.236.244; 3.P.237.228; 3.P.237.229; 3.P.237.230; 3.P.237.231;3.P.237.236; 3.P.237.237; 3.P.237.238; 3.P.237.239; 3.P.237.154;3.P.237.157; 3.P.237.166; 3.P.237.169; 3.P.237.172; 3.P.237.175;3.P.237.240; 3.P.237.244; 3.P.238.228; 3.P.238.229; 3.P.238.230;3.P.238.231; 3.P.238.236; 3.P.238.237; 3.P.238.238; 3.P.238.239;3.P.238.154; 3.P.238.157; 3.P.238.166; 3.P.238.169; 3.P.238.172;3.P.238.175; 3.P.238.240; 3.P.238.244; 3.P.239.228; 3.P.239.229;3.P.239.230; 3.P.239.231; 3.P.239.236; 3.P.239.237; 3.P.239.238;3.P.239.239; 3.P.239.154; 3.P.239.157; 3.P.239.166; 3.P.239.169;3.P.239.172; 3.P.239.175; 3.P.239.240; 3.P.239.244; 3.P.154.228;3.P.154.229; 3.P.154.230; 3.P.154.231; 3.P.154.236; 3.P.154.237;3.P.154.238; 3.P.154.239; 3.P.154.154; 3.P.154.157; 3.P.154.166;3.P.154.169; 3.P.154.172; 3.P.154.175; 3.P.154.240; 3.P.154.244;3.P.157.228; 3.P.157.229; 3.P.157.230; 3.P.157.231; 3.P.157.236;3.P.157.237; 3.P.157.238; 3.P.157.239; 3.P.157.154; 3.P.157.157;3.P.157.166; 3.P.157.169; 3.P.157.172; 3.P.157.175; 3.P.157.240;3.P.157.244; 3.P.166.228; 3.P.166.229; 3.P.166.230; 3.P.166.231;3.P.166.236; 3.P.166.237; 3.P.166.238; 3.P.166.239; 3.P.166.154;3.P.166.157; 3.P.166.166; 3.P.166.169; 3.P.166.172; 3.P.166.175;3.P.166.240; 3.P.166.244; 3.P.169.228; 3.P.169.229; 3.P.169.230;3.P.169.231; 3.P.169.236; 3.P.169.237; 3.P.169.238; 3.P.169.239;3.P.169.154; 3.P.169.157; 3.P.169.166; 3.P.169.169; 3.P.169.172;3.P.169.175; 3.P.169.240; 3.P.169.244; 3.P.172.228; 3.P.172.229;3.P.172.230; 3.P.172.231; 3.P.172.236; 3.P.172.237; 3.P.172.238;3.P.172.239; 3.P.172.154; 3.P.172.157; 3.P.172.166; 3.P.172.169;3.P.172.172; 3.P.172.175; 3.P.172.240; 3.P.172.244; 3.P.175.228;3.P.175.229; 3.P.175.230; 3.P.175.231; 3.P.175.236; 3.P.175.237;3.P.175.238; 3.P.175.239; 3.P.175.154; 3.P.175.157; 3.P.175.166;3.P.175.169; 3.P.175.172; 3.P.175.175; 3.P.175.240; 3.P.175.244;3.P.240.228; 3.P.240.229; 3.P.240.230; 3.P.240.231; 3.P.240.236;3.P.240.237; 3.P.240.238; 3.P.240.239; 3.P.240.154; 3.P.240.157;3.P.240.166; 3.P.240.169; 3.P.240.172; 3.P.240.175; 3.P.240.240;3.P.240.244; 3.P.244.228; 3.P.244.229; 3.P.244.230; 3.P.244.231;3.P.244.236; 3.P.244.237; 3.P.244.238; 3.P.244.239; 3.P.244.154;3.P.244.157; 3.P.244.166; 3.P.244.169; 3.P.244.172; 3.P.244.175;3.P.244.240; 3.P.244.244; Prodrugs of 3.U 3.U.228.228; 3.U.228.229;3.U.228.230; 3.U.228.231; 3.U.228.236; 3.U.228.237; 3.U.228.238;3.U.228.239; 3.U.228.154; 3.U.228.157; 3.U.228.166; 3.U.228.169;3.U.228.172; 3.U.228.175; 3.U.228.240; 3.U.228.244; 3.U.229.228;3.U.229.229; 3.U.229.230; 3.U.229.231; 3.U.229.236; 3.U.229.237;3.U.229.238; 3.U.229.239; 3.U.229.154; 3.U.229.157; 3.U.229.166;3.U.229.169; 3.U.229.172; 3.U.229.175; 3.U.229.240; 3.U.229.244;3.U.230.228; 3.U.230.229; 3.U.230.230; 3.U.230.231; 3.U.230.236;3.U.230.237; 3.U.230.238; 3.U.230.239; 3.U.230.154; 3.U.230.157;3.U.230.166; 3.U.230.169; 3.U.230.172; 3.U.230.175; 3.U.230.240;3.U.230.244; 3.U.231.228; 3.U.231.229; 3.U.231.230; 3.U.231.231;3.U.231.236; 3.U.231.237; 3.U.231.238; 3.U.231.239; 3.U.231.154;3.U.231.157; 3.U.231.166; 3.U.231.169; 3.U.231.172; 3.U.231.175;3.U.231.240; 3.U.231.244; 3.U.236.228; 3.U.236.229; 3.U.236.230;3.U.236.231; 3.U.236.236; 3.U.236.237; 3.U.236.238; 3.U.236.239;3.U.236.154; 3.U.236.157; 3.U.236.166; 3.U.236.169; 3.U.236.172;3.U.236.175; 3.U.236.240; 3.U.236.244; 3.U.237.228; 3.U.237.229;3.U.237.230; 3.U.237.231; 3.U.237.236; 3.U.237.237; 3.U.237.238;3.U.237.239; 3.U.237.154; 3.U.237.157; 3.U.237.166; 3.U.237.169;3.U.237.172; 3.U.237.175; 3.U.237.240; 3.U.237.244; 3.U.238.228;3.U.238.229; 3.U.238.230; 3.U.238.231; 3.U.238.236; 3.U.238.237;3.U.238.238; 3.U.238.239; 3.U.238.154; 3.U.238.157; 3.U.238.166;3.U.238.169; 3.U.238.172; 3.U.238.175; 3.U.238.240; 3.U.238.244;3.U.239.228; 3.U.239.229; 3.U.239.230; 3.U.239.231; 3.U.239.236;3.U.239.237; 3.U.239.238; 3.U.239.239; 3.U.239.154; 3.U.239.157;3.U.239.166; 3.U.239.169; 3.U.239.172; 3.U.239.175; 3.U.239.240;3.U.239.244; 3.U.154.228; 3.U.154.229; 3.U.154.230; 3.U.154.231;3.U.154.236; 3.U.154.237; 3.U.154.238; 3.U.154.239; 3.U.154.154;3.U.154.157; 3.U.154.166; 3.U.154.169; 3.U.154.172; 3.U.154.175;3.U.154.240; 3.U.154.244; 3.U.157.228; 3.U.157.229; 3.U.157.230;3.U.157.231; 3.U.157.236; 3.U.157.237; 3.U.157.238; 3.U.157.239;3.U.157.154; 3.U.157.157; 3.U.157.166; 3.U.157.169; 3.U.157.172;3.U.157.175; 3.U.157.240; 3.U.157.244; 3.U.166.228; 3.U.166.229;3.U.166.230; 3.U.166.231; 3.U.166.236; 3.U.166.237; 3.U.166.238;3.U.166.239; 3.U.166.154; 3.U.166.157; 3.U.166.166; 3.U.166.169;3.U.166.172; 3.U.166.175; 3.U.166.240; 3.U.166.244; 3.U.169.228;3.U.169.229; 3.U.169.230; 3.U.169.231; 3.U.169.236; 3.U.169.237;3.U.169.238; 3.U.169.239; 3.U.169.154; 3.U.169.157; 3.U.169.166;3.U.169.169; 3.U.169.172; 3.U.169.175; 3.U.169.240; 3.U.169.244;3.U.172.228; 3.U.172.229; 3.U.172.230; 3.U.172.231; 3.U.172.236;3.U.172.237; 3.U.172.238; 3.U.172.239; 3.U.172.154; 3.U.172.157;3.U.172.166; 3.U.172.169; 3.U.172.172; 3.U.172.175; 3.U.172.240;3.U.172.244; 3.U.175.228; 3.U.175.229; 3.U.175.230; 3.U.175.231;3.U.175.236; 3.U.175.237; 3.U.175.238; 3.U.175.239; 3.U.175.154;3.U.175.157; 3.U.175.166; 3.U.175.169; 3.U.175.172; 3.U.175.175;3.U.175.240; 3.U.175.244; 3.U.240.228; 3.U.240.229; 3.U.240.230;3.U.240.231; 3.U.240.236; 3.U.240.237; 3.U.240.238; 3.U.240.239;3.U.240.154; 3.U.240.157; 3.U.240.166; 3.U.240.169; 3.U.240.172;3.U.240.175; 3.U.240.240; 3.U.240.244; 3.U.244.228; 3.U.244.229;3.U.244.230; 3.U.244.231; 3.U.244.236; 3.U.244.237; 3.U.244.238;3.U.244.239; 3.U.244.154; 3.U.244.157; 3.U.244.166; 3.U.244.169;3.U.244.172; 3.U.244.175; 3.U.244.240; 3.U.244.244; Prodrugs of 3.W3.W.228.228; 3.W.228.229; 3.W.228.230; 3.W.228.231; 3.W.228.236;3.W.228.237; 3.W.228.238; 3.W.228.239; 3.W.228.154; 3.W.228.157;3.W.228.166; 3.W.228.169; 3.W.228.172; 3.W.228.175; 3.W.228.240;3.W.228.244; 3.W.229.228; 3.W.229.229; 3.W.229.230; 3.W.229.231;3.W.229.236; 3.W.229.237; 3.W.229.238; 3.W.229.239; 3.W.229.154;3.W.229.157; 3.W.229.166; 3.W.229.169; 3.W.229.172; 3.W.229.175;3.W.229.240; 3.W.229.244; 3.W.230.228; 3.W.230.229; 3.W.230.230;3.W.230.231; 3.W.230.236; 3.W.230.237; 3.W.230.238; 3.W.230.239;3.W.230.154; 3.W.230.157; 3.W.230.166; 3.W.230.169; 3.W.230.172;3.W.230.175; 3.W.230.240; 3.W.230.244; 3.W.231.228; 3.W.231.229;3.W.231.230; 3.W.231.231; 3.W.231.236; 3.W.231.237; 3.W.231.238;3.W.231.239; 3.W.231.154; 3.W.231.157; 3.W.231.166; 3.W.231.169;3.W.231.172; 3.W.231.175; 3.W.231.240; 3.W.231.244; 3.W.236.228;3.W.236.229; 3.W.236.230; 3.W.236.231; 3.W.236.236; 3.W.236.237;3.W.236.238; 3.W.236.239; 3.W.236.154; 3.W.236.157; 3.W.236.166;3.W.236.169; 3.W.236.172; 3.W.236.175; 3.W.236.240; 3.W.236.244;3.W.237.228; 3.W.237.229; 3.W.237.230; 3.W.237.231; 3.W.237.236;3.W.237.237; 3.W.237.238; 3.W.237.239; 3.W.237.154; 3.W.237.157;3.W.237.166; 3.W.237.169; 3.W.237.172; 3.W.237.175; 3.W.237.240;3.W.237.244; 3.W.238.228; 3.W.238.229; 3.W.238.230; 3.W.238.231;3.W.238.236; 3.W.238.237; 3.W.238.238; 3.W.238.239; 3.W.238.154;3.W.238.157; 3.W.238.166; 3.W.238.169; 3.W.238.172; 3.W.238.175;3.W.238.240; 3.W.238.244; 3.W.239.228; 3.W.239.229; 3.W.239.230;3.W.239.231; 3.W.239.236; 3.W.239.237; 3.W.239.238; 3.W.239.239;3.W.239.154; 3.W.239.157; 3.W.239.166; 3.W.239.169; 3.W.239.172;3.W.239.175; 3.W.239.240; 3.W.239.244; 3.W.154.228; 3.W.154.229;3.W.154.230; 3.W.154.231; 3.W.154.236; 3.W.154.237; 3.W.154.238;3.W.154.239; 3.W.154.154; 3.W.154.157; 3.W.154.166; 3.W.154.169;3.W.154.172; 3.W.154.175; 3.W.154.240; 3.W.154.244; 3.W.157.228;3.W.157.229; 3.W.157.230; 3.W.157.231; 3.W.157.236; 3.W.157.237;3.W.157.238; 3.W.157.239; 3.W.157.154; 3.W.157.157; 3.W.157.166;3.W.157.169; 3.W.157.172; 3.W.157.175; 3.W.157.240; 3.W.157.244;3.W.166.228; 3.W.166.229; 3.W.166.230; 3.W.166.231; 3.W.166.236;3.W.166.237; 3.W.166.238; 3.W.166.239; 3.W.166.154; 3.W.166.157;3.W.166.166; 3.W.166.169; 3.W.166.172; 3.W.166.175; 3.W.166.240;3.W.166.244; 3.W.169.228; 3.W.169.229; 3.W.169.230; 3.W.169.231;3.W.169.236; 3.W.169.237; 3.W.169.238; 3.W.169.239; 3.W.169.154;3.W.169.157; 3.W.169.166; 3.W.169.169; 3.W.169.172; 3.W.169.175;3.W.169.240; 3.W.169.244; 3.W.172.228; 3.W.172.229; 3.W.172.230;3.W.172.231; 3.W.172.236; 3.W.172.237; 3.W.172.238; 3.W.172.239;3.W.172.154; 3.W.172.157; 3.W.172.166; 3.W.172.169; 3.W.172.172;3.W.172.175; 3.W.172.240; 3.W.172.244; 3.W.175.228; 3.W.175.229;3.W.175.230; 3.W.175.231; 3.W.175.236; 3.W.175.237; 3.W.175.238;3.W.175.239; 3.W.175.154; 3.W.175.157; 3.W.175.166; 3.W.175.169;3.W.175.172; 3.W.175.175; 3.W.175.240; 3.W.175.244; 3.W.240.228;3.W.240.229; 3.W.240.230; 3.W.240.231; 3.W.240.236; 3.W.240.237;3.W.240.238; 3.W.240.239; 3.W.240.154; 3.W.240.157; 3.W.240.166;3.W.240.169; 3.W.240.172; 3.W.240.175; 3.W.240.240; 3.W.240.244;3.W.244.228; 3.W.244.229; 3.W.244.230; 3.W.244.231; 3.W.244.236;3.W.244.237; 3.W.244.238; 3.W.244.239; 3.W.244.154; 3.W.244.157;3.W.244.166; 3.W.244.169; 3.W.244.172; 3.W.244.175; 3.W.244.240;3.W.244.244; Prodrugs of 3.Y 3.Y.228.228; 3.Y.228.229; 3.Y.228.230;3.Y.228.231; 3.Y.228.236; 3.Y.228.237; 3.Y.228.238; 3.Y.228.239;3.Y.228.154; 3.Y.228.157; 3.Y.228.166; 3.Y.228.169; 3.Y.228.172;3.Y.228.175; 3.Y.228.240; 3.Y.228.244; 3.Y.229.228; 3.Y.229.229;3.Y.229.230; 3.Y.229.231; 3.Y.229.236; 3.Y.229.237; 3.Y.229.238;3.Y.229.239; 3.Y.229.154; 3.Y.229.157; 3.Y.229.166; 3.Y.229.169;3.Y.229.172; 3.Y.229.175; 3.Y.229.240; 3.Y.229.244; 3.Y.230.228;3.Y.230.229; 3.Y.230.230; 3.Y.230.231; 3.Y.230.236; 3.Y.230.237;3.Y.230.238; 3.Y.230.239; 3.Y.230.154; 3.Y.230.157; 3.Y.230.166;3.Y.230.169; 3.Y.230.172; 3.Y.230.175; 3.Y.230.240; 3.Y.230.244;3.Y.231.228; 3.Y.231.229; 3.Y.231.230; 3.Y.231.231; 3.Y.231.236;3.Y.231.237; 3.Y.231.238; 3.Y.231.239; 3.Y.231.154; 3.Y.231.157;3.Y.231.166; 3.Y.231.169; 3.Y.231.172; 3.Y.231.175; 3.Y.231.240;3.Y.231.244; 3.Y.236.228; 3.Y.236.229; 3.Y.236.230; 3.Y.236.231;3.Y.236.236; 3.Y.236.237; 3.Y.236.238; 3.Y.236.239; 3.Y.236.154;3.Y.236.157; 3.Y.236.166; 3.Y.236.169; 3.Y.236.172; 3.Y.236.175;3.Y.236.240; 3.Y.236.244; 3.Y.237.228; 3.Y.237.229; 3.Y.237.230;3.Y.237.231; 3.Y.237.236; 3.Y.237.237; 3.Y.237.238; 3.Y.237.239;3.Y.237.154; 3.Y.237.157; 3.Y.237.166; 3.Y.237.169; 3.Y.237.172;3.Y.237.175; 3.Y.237.240; 3.Y.237.244; 3.Y.238.228; 3.Y.238.229;3.Y.238.230; 3.Y.238.231; 3.Y.238.236; 3.Y.238.237; 3.Y.238.238;3.Y.238.239; 3.Y.238.154; 3.Y.238.157; 3.Y.238.166; 3.Y.238.169;3.Y.238.172; 3.Y.238.175; 3.Y.238.240; 3.Y.238.244; 3.Y.239.228;3.Y.239.229; 3.Y.239.230; 3.Y.239.231; 3.Y.239.236; 3.Y.239.237;3.Y.239.238; 3.Y.239.239; 3.Y.239.154; 3.Y.239.157; 3.Y.239.166;3.Y.239.169; 3.Y.239.172; 3.Y.239.175; 3.Y.239.240; 3.Y.239.244;3.Y.154.228; 3.Y.154.229; 3.Y.154.230; 3.Y.154.231; 3.Y.154.236;3.Y.154.237; 3.Y.154.238; 3.Y.154.239; 3.Y.154.154; 3.Y.154.157;3.Y.154.166; 3.Y.154.169; 3.Y.154.172; 3.Y.154.175; 3.Y.154.240;3.Y.154.244; 3.Y.157.228; 3.Y.157.229; 3.Y.157.230; 3.Y.157.231;3.Y.157.236; 3.Y.157.237; 3.Y.157.238; 3.Y.157.239; 3.Y.157.154;3.Y.157.157; 3.Y.157.166; 3.Y.157.169; 3.Y.157.172; 3.Y.157.175;3.Y.157.240; 3.Y.157.244; 3.Y.166.228; 3.Y.166.229; 3.Y.166.230;3.Y.166.231; 3.Y.166.236; 3.Y.166.237; 3.Y.166.238; 3.Y.166.239;3.Y.166.154; 3.Y.166.157; 3.Y.166.166; 3.Y.166.169; 3.Y.166.172;3.Y.166.175; 3.Y.166.240; 3.Y.166.244; 3.Y.169.228; 3.Y.169.229;3.Y.169.230; 3.Y.169.231; 3.Y.169.236; 3.Y.169.237; 3.Y.169.238;3.Y.169.239; 3.Y.169.154; 3.Y.169.157; 3.Y.169.166; 3.Y.169.169;3.Y.169.172; 3.Y.169.175; 3.Y.169.240; 3.Y.169.244; 3.Y.172.228;3.Y.172.229; 3.Y.172.230; 3.Y.172.231; 3.Y.172.236; 3.Y.172.237;3.Y.172.238; 3.Y.172.239; 3.Y.172.154; 3.Y.172.157; 3.Y.172.166;3.Y.172.169; 3.Y.172.172; 3.Y.172.175; 3.Y.172.240; 3.Y.172.244;3.Y.175.228; 3.Y.175.229; 3.Y.175.230; 3.Y.175.231; 3.Y.175.236;3.Y.175.237; 3.Y.175.238; 3.Y.175.239; 3.Y.175.154; 3.Y.175.157;3.Y.175.166; 3.Y.175.169; 3.Y.175.172; 3.Y.175.175; 3.Y.175.240;3.Y.175.244; 3.Y.240.228; 3.Y.240.229; 3.Y.240.230; 3.Y.240.231;3.Y.240.236; 3.Y.240.237; 3.Y.240.238; 3.Y.240.239; 3.Y.240.154;3.Y.240.157; 3.Y.240.166; 3.Y.240.169; 3.Y.240.172; 3.Y.240.175;3.Y.240.240; 3.Y.240.244; 3.Y.244.228; 3.Y.244.229; 3.Y.244.230;3.Y.244.231; 3.Y.244.236; 3.Y.244.237; 3.Y.244.238; 3.Y.244.239;3.Y.244.154; 3.Y.244.157; 3.Y.244.166; 3.Y.244.169; 3.Y.244.172;3.Y.244.175; 3.Y.244.240; 3.Y.244.244; Prodrugs of 4.B 4.B.228.228;4.B.228.229; 4.B.228.230; 4.B.228.231; 4.B.228.236; 4.B.228.237;4.B.228.238; 4.B.228.239; 4.B.228.154; 4.B.228.157; 4.B.228.166;4.B.228.169; 4.B.228.172; 4.B.228.175; 4.B.228.240; 4.B.228.244;4.B.229.228; 4.B.229.229; 4.B.229.230; 4.B.229.231; 4.B.229.236;4.B.229.237; 4.B.229.238; 4.B.229.239; 4.B.229.154; 4.B.229.157;4.B.229.166; 4.B.229.169; 4.B.229.172; 4.B.229.175; 4.B.229.240;4.B.229.244; 4.B.230.228; 4.B.230.229; 4.B.230.230; 4.B.230.231;4.B.230.236; 4.B.230.237; 4.B.230.238; 4.B.230.239; 4.B.230.154;4.B.230.157; 4.B.230.166; 4.B.230.169; 4.B.230.172; 4.B.230.175;4.B.230.240; 4.B.230.244; 4.B.231.228; 4.B.231.229; 4.B.231.230;4.B.231.231; 4.B.231.236; 4.B.231.237; 4.B.231.238; 4.B.231.239;4.B.231.154; 4.B.231.157; 4.B.231.166; 4.B.231.169; 4.B.231.172;4.B.231.175; 4.B.231.240; 4.B.231.244; 4.B.236.228; 4.B.236.229;4.B.236.230; 4.B.236.231; 4.B.236.236; 4.B.236.237; 4.B.236.238;4.B.236.239; 4.B.236.154; 4.B.236.157; 4.B.236.166; 4.B.236.169;4.B.236.172; 4.B.236.175; 4.B.236.240; 4.B.236.244; 4.B.237.228;4.B.237.229; 4.B.237.230; 4.B.237.231; 4.B.237.236; 4.B.237.237;4.B.237.238; 4.B.237.239; 4.B.237.154; 4.B.237.157; 4.B.237.166;4.B.237.169; 4.B.237.172; 4.B.237.175; 4.B.237.240; 4.B.237.244;4.B.238.228; 4.B.238.229; 4.B.238.230; 4.B.238.231; 4.B.238.236;4.B.238.237; 4.B.238.238; 4.B.238.239; 4.B.238.154; 4.B.238.157;4.B.238.166; 4.B.238.169; 4.B.238.172; 4.B.238.175; 4.B.238.240;4.B.238.244; 4.B.239.228; 4.B.239.229; 4.B.239.230; 4.B.239.231;4.B.239.236; 4.B.239.237; 4.B.239.238; 4.B.239.239; 4.B.239.154;4.B.239.157; 4.B.239.166; 4.B.239.169; 4.B.239.172; 4.B.239.175;4.B.239.240; 4.B.239.244; 4.B.154.228; 4.B.154.229; 4.B.154.230;4.B.154.231; 4.B.154.236; 4.B.154.237; 4.B.154.238; 4.B.154.239;4.B.154.154; 4.B.154.157; 4.B.154.166; 4.B.154.169; 4.B.154.172;4.B.154.175; 4.B.154.240; 4.B.154.244; 4.B.157.228; 4.B.157.229;4.B.157.230; 4.B.157.231; 4.B.157.236; 4.B.157.237; 4.B.157.238;4.B.157.239; 4.B.157.154; 4.B.157.157; 4.B.157.166; 4.B.157.169;4.B.157.172; 4.B.157.175; 4.B.157.240; 4.B.157.244; 4.B.166.228;4.B.166.229; 4.B.166.230; 4.B.166.231; 4.B.166.236; 4.B.166.237;4.B.166.238; 4.B.166.239; 4.B.166.154; 4.B.166.157; 4.B.166.166;4.B.166.169; 4.B.166.172; 4.B.166.175; 4.B.166.240; 4.B.166.244;4.B.169.228; 4.B.169.229; 4.B.169.230; 4.B.169.231; 4.B.169.236;4.B.169.237; 4.B.169.238; 4.B.169.239; 4.B.169.154; 4.B.169.157;4.B.169.166; 4.B.169.169; 4.B.169.172; 4.B.169.175; 4.B.169.240;4.B.169.244; 4.B.172.228; 4.B.172.229; 4.B.172.230; 4.B.172.231;4.B.172.236; 4.B.172.237; 4.B.172.238; 4.B.172.239; 4.B.172.154;4.B.172.157; 4.B.172.166; 4.B.172.169; 4.B.172.172; 4.B.172.175;4.B.172.240; 4.B.172.244; 4.B.175.228; 4.B.175.229; 4.B.175.230;4.B.175.231; 4.B.175.236; 4.B.175.237; 4.B.175.238; 4.B.175.239;4.B.175.154; 4.B.175.157; 4.B.175.166; 4.B.175.169; 4.B.175.172;4.B.175.175; 4.B.175.240; 4.B.175.244; 4.B.240.228; 4.B.240.229;4.B.240.230; 4.B.240.231; 4.B.240.236; 4.B.240.237; 4.B.240.238;4.B.240.239; 4.B.240.154; 4.B.240.157; 4.B.240.166; 4.B.240.169;4.B.240.172; 4.B.240.175; 4.B.240.240; 4.B.240.244; 4.B.244.228;4.B.244.229; 4.B.244.230; 4.B.244.231; 4.B.244.236; 4.B.244.237;4.B.244.238; 4.B.244.239; 4.B.244.154; 4.B.244.157; 4.B.244.166;4.B.244.169; 4.B.244.172; 4.B.244.175; 4.B.244.240; 4.B.244.244;Prodrugs of 4.D 4.D.228.228; 4.D.228.229; 4.D.228.230; 4.D.228.231;4.D.228.236; 4.D.228.237; 4.D.228.238; 4.D.228.239; 4.D.228.154;4.D.228.157; 4.D.228.166; 4.D.228.169; 4.D.228.172; 4.D.228.175;4.D.228.240; 4.D.228.244; 4.D.229.228; 4.D.229.229; 4.D.229.230;4.D.229.231; 4.D.229.236; 4.D.229.237; 4.D.229.238; 4.D.229.239;4.D.229.154; 4.D.229.157; 4.D.229.166; 4.D.229.169; 4.D.229.172;4.D.229.175; 4.D.229.240; 4.D.229.244; 4.D.230.228; 4.D.230.229;4.D.230.230; 4.D.230.231; 4.D.230.236; 4.D.230.237; 4.D.230.238;4.D.230.239; 4.D.230.154; 4.D.230.157; 4.D.230.166; 4.D.230.169;4.D.230.172; 4.D.230.175; 4.D.230.240; 4.D.230.244; 4.D.231.228;4.D.231.229; 4.D.231.230; 4.D.231.231; 4.D.231.236; 4.D.231.237;4.D.231.238; 4.D.231.239; 4.D.231.154; 4.D.231.157; 4.D.231.166;4.D.231.169; 4.D.231.172; 4.D.231.175; 4.D.231.240; 4.D.231.244;4.D.236.228; 4.D.236.229; 4.D.236.230; 4.D.236.231; 4.D.236.236;4.D.236.237; 4.D.236.238; 4.D.236.239; 4.D.236.154; 4.D.236.157;4.D.236.166; 4.D.236.169; 4.D.236.172; 4.D.236.175; 4.D.236.240;4.D.236.244; 4.D.237.228; 4.D.237.229; 4.D.237.230; 4.D.237.231;4.D.237.236; 4.D.237.237; 4.D.237.238; 4.D.237.239; 4.D.237.154;4.D.237.157; 4.D.237.166; 4.D.237.169; 4.D.237.172; 4.D.237.175;4.D.237.240; 4.D.237.244; 4.D.238.228; 4.D.238.229; 4.D.238.230;4.D.238.231; 4.D.238.236; 4.D.238.237; 4.D.238.238; 4.D.238.239;4.D.238.154; 4.D.238.157; 4.D.238.166; 4.D.238.169; 4.D.238.172;4.D.238.175; 4.D.238.240; 4.D.238.244; 4.D.239.228; 4.D.239.229;4.D.239.230; 4.D.239.231; 4.D.239.236; 4.D.239.237; 4.D.239.238;4.D.239.239; 4.D.239.154; 4.D.239.157; 4.D.239.166; 4.D.239.169;4.D.239.172; 4.D.239.175; 4.D.239.240; 4.D.239.244; 4.D.154.228;4.D.154.229; 4.D.154.230; 4.D.154.231; 4.D.154.236; 4.D.154.237;4.D.154.238; 4.D.154.239; 4.D.154.154; 4.D.154.157; 4.D.154.166;4.D.154.169; 4.D.154.172; 4.D.154.175; 4.D.154.240; 4.D.154.244;4.D.157.228; 4.D.157.229; 4.D.157.230; 4.D.157.231; 4.D.157.236;4.D.157.237; 4.D.157.238; 4.D.157.239; 4.D.157.154; 4.D.157.157;4.D.157.166; 4.D.157.169; 4.D.157.172; 4.D.157.175; 4.D.157.240;4.D.157.244; 4.D.166.228; 4.D.166.229; 4.D.166.230; 4.D.166.231;4.D.166.236; 4.D.166.237; 4.D.166.238; 4.D.166.239; 4.D.166.154;4.D.166.157; 4.D.166.166; 4.D.166.169; 4.D.166.172; 4.D.166.175;4.D.166.240; 4.D.166.244; 4.D.169.228; 4.D.169.229; 4.D.169.230;4.D.169.231; 4.D.169.236; 4.D.169.237; 4.D.169.238; 4.D.169.239;4.D.169.154; 4.D.169.157; 4.D.169.166; 4.D.169.169; 4.D.169.172;4.D.169.175; 4.D.169.240; 4.D.169.244; 4.D.172.228; 4.D.172.229;4.D.172.230; 4.D.172.231; 4.D.172.236; 4.D.172.237; 4.D.172.238;4.D.172.239; 4.D.172.154; 4.D.172.157; 4.D.172.166; 4.D.172.169;4.D.172.172; 4.D.172.175; 4.D.172.240; 4.D.172.244; 4.D.175.228;4.D.175.229; 4.D.175.230; 4.D.175.231; 4.D.175.236; 4.D.175.237;4.D.175.238; 4.D.175.239; 4.D.175.154; 4.D.175.157; 4.D.175.166;4.D.175.169; 4.D.175.172; 4.D.175.175; 4.D.175.240; 4.D.175.244;4.D.240.228; 4.D.240.229; 4.D.240.230; 4.D.240.231; 4.D.240.236;4.D.240.237; 4.D.240.238; 4.D.240.239; 4.D.240.154; 4.D.240.157;4.D.240.166; 4.D.240.169; 4.D.240.172; 4.D.240.175; 4.D.240.240;4.D.240.244; 4.D.244.228; 4.D.244.229; 4.D.244.230; 4.D.244.231;4.D.244.236; 4.D.244.237; 4.D.244.238; 4.D.244.239; 4.D.244.154;4.D.244.157; 4.D.244.166; 4.D.244.169; 4.D.244.172; 4.D.244.175;4.D.244.240; 4.D.244.244; Prodrugs of 4.E 4.E.228.228; 4.E.228.229;4.E.228.230; 4.E.228.231; 4.E.228.236; 4.E.228.237; 4.E.228.238;4.E.228.239; 4.E.228.154; 4.E.228.157; 4.E.228.166; 4.E.228.169;4.E.228.172; 4.E.228.175; 4.E.228.240; 4.E.228.244; 4.E.229.228;4.E.229.229; 4.E.229.230; 4.E.229.231; 4.E.229.236; 4.E.229.237;4.E.229.238; 4.E.229.239; 4.E.229.154; 4.E.229.157; 4.E.229.166;4.E.229.169; 4.E.229.172; 4.E.229.175; 4.E.229.240; 4.E.229.244;4.E.230.228; 4.E.230.229; 4.E.230.230; 4.E.230.231; 4.E.230.236;4.E.230.237; 4.E.230.238; 4.E.230.239; 4.E.230.154; 4.E.230.157;4.E.230.166; 4.E.230.169; 4.E.230.172; 4.E.230.175; 4.E.230.240;4.E.230.244; 4.E.231.228; 4.E.231.229; 4.E.231.230; 4.E.231.231;4.E.231.236; 4.E.231.237; 4.E.231.238; 4.E.231.239; 4.E.231.154;4.E.231.157; 4.E.231.166; 4.E.231.169; 4.E.231.172; 4.E.231.175;4.E.231.240; 4.E.231.244; 4.E.236.228; 4.E.236.229; 4.E.236.230;4.E.236.231; 4.E.236.236; 4.E.236.237; 4.E.236.238; 4.E.236.239;4.E.236.154; 4.E.236.157; 4.E.236.166; 4.E.236.169; 4.E.236.172;4.E.236.175; 4.E.236.240; 4.E.236.244; 4.E.237.228; 4.E.237.229;4.E.237.230; 4.E.237.231; 4.E.237.236; 4.E.237.237; 4.E.237.238;4.E.237.239; 4.E.237.154; 4.E.237.157; 4.E.237.166; 4.E.237.169;4.E.237.172; 4.E.237.175; 4.E.237.240; 4.E.237.244; 4.E.238.228;4.E.238.229; 4.E.238.230; 4.E.238.231; 4.E.238.236; 4.E.238.237;4.E.238.238; 4.E.238.239; 4.E.238.154; 4.E.238.157; 4.E.238.166;4.E.238.169; 4.E.238.172; 4.E.238.175; 4.E.238.240; 4.E.238.244;4.E.239.228; 4.E.239.229; 4.E.239.230; 4.E.239.231; 4.E.239.236;4.E.239.237; 4.E.239.238; 4.E.239.239; 4.E.239.154; 4.E.239.157;4.E.239.166; 4.E.239.169; 4.E.239.172; 4.E.239.175; 4.E.239.240;4.E.239.244; 4.E.154.228; 4.E.154.229; 4.E.154.230; 4.E.154.231;4.E.154.236; 4.E.154.237; 4.E.154.238; 4.E.154.239; 4.E.154.154;4.E.154.157; 4.E.154.166; 4.E.154.169; 4.E.154.172; 4.E.154.175;4.E.154.240; 4.E.154.244; 4.E.157.228; 4.E.157.229; 4.E.157.230;4.E.157.231; 4.E.157.236; 4.E.157.237; 4.E.157.238; 4.E.157.239;4.E.157.154; 4.E.157.157; 4.E.157.166; 4.E.157.169; 4.E.157.172;4.E.157.175; 4.E.157.240; 4.E.157.244; 4.E.166.228; 4.E.166.229;4.E.166.230; 4.E.166.231; 4.E.166.236; 4.E.166.237; 4.E.166.238;4.E.166.239; 4.E.166.154; 4.E.166.157; 4.E.166.166; 4.E.166.169;4.E.166.172; 4.E.166.175; 4.E.166.240; 4.E.166.244; 4.E.169.228;4.E.169.229; 4.E.169.230; 4.E.169.231; 4.E.169.236; 4.E.169.237;4.E.169.238; 4.E.169.239; 4.E.169.154; 4.E.169.157; 4.E.169.166;4.E.169.169; 4.E.169.172; 4.E.169.175; 4.E.169.240; 4.E.169.244;4.E.172.228; 4.E.172.229; 4.E.172.230; 4.E.172.231; 4.E.172.236;4.E.172.237; 4.E.172.238; 4.E.172.239; 4.E.172.154; 4.E.172.157;4.E.172.166; 4.E.172.169; 4.E.172.172; 4.E.172.175; 4.E.172.240;4.E.172.244; 4.E.175.228; 4.E.175.229; 4.E.175.230; 4.E.175.231;4.E.175.236; 4.E.175.237; 4.E.175.238; 4.E.175.239; 4.E.175.154;4.E.175.157; 4.E.175.166; 4.E.175.169; 4.E.175.172; 4.E.175.175;4.E.175.240; 4.E.175.244; 4.E.240.228; 4.E.240.229; 4.E.240.230;4.E.240.231; 4.E.240.236; 4.E.240.237; 4.E.240.238; 4.E.240.239;4.E.240.154; 4.E.240.157; 4.E.240.166; 4.E.240.169; 4.E.240.172;4.E.240.175; 4.E.240.240; 4.E.240.244; 4.E.244.228; 4.E.244.229;4.E.244.230; 4.E.244.231; 4.E.244.236; 4.E.244.237; 4.E.244.238;4.E.244.239; 4.E.244.154; 4.E.244.157; 4.E.244.166; 4.E.244.169;4.E.244.172; 4.E.244.175; 4.E.244.240; 4.E.244.244; Prodrugs of 4.G4.G.228.228; 4.G.228.229; 4.G.228.230; 4.G.228.231; 4.G.228.236;4.G.228.237; 4.G.228.238; 4.G.228.239; 4.G.228.154; 4.G.228.157;4.G.228.166; 4.G.228.169; 4.G.228.172; 4.G.228.175; 4.G.228.240;4.G.228.244; 4.G.229.228; 4.G.229.229; 4.G.229.230; 4.G.229.231;4.G.229.236; 4.G.229.237; 4.G.229.238; 4.G.229.239; 4.G.229.154;4.G.229.157; 4.G.229.166; 4.G.229.169; 4.G.229.172; 4.G.229.175;4.G.229.240; 4.G.229.244; 4.G.230.228; 4.G.230.229; 4.G.230.230;4.G.230.231; 4.G.230.236; 4.G.230.237; 4.G.230.238; 4.G.230.239;4.G.230.154; 4.G.230.157; 4.G.230.166; 4.G.230.169; 4.G.230.172;4.G.230.175; 4.G.230.240; 4.G.230.244; 4.G.231.228; 4.G.231.229;4.G.231.230; 4.G.231.231; 4.G.231.236; 4.G.231.237; 4.G.231.238;4.G.231.239; 4.G.231.154; 4.G.231.157; 4.G.231.166; 4.G.231.169;4.G.231.172; 4.G.231.175; 4.G.231.240; 4.G.231.244; 4.G.236.228;4.G.236.229; 4.G.236.230; 4.G.236.231; 4.G.236.236; 4.G.236.237;4.G.236.238; 4.G.236.239; 4.G.236.154; 4.G.236.157; 4.G.236.166;4.G.236.169; 4.G.236.172; 4.G.236.175; 4.G.236.240; 4.G.236.244;4.G.237.228; 4.G.237.229; 4.G.237.230; 4.G.237.231; 4.G.237.236;4.G.237.237; 4.G.237.238; 4.G.237.239; 4.G.237.154; 4.G.237.157;4.G.237.166; 4.G.237.169; 4.G.237.172; 4.G.237.175; 4.G.237.240;4.G.237.244; 4.G.238.228; 4.G.238.229; 4.G.238.230; 4.G.238.231;4.G.238.236; 4.G.238.237; 4.G.238.238; 4.G.238.239; 4.G.238.154;4.G.238.157; 4.G.238.166; 4.G.238.169; 4.G.238.172; 4.G.238.175;4.G.238.240; 4.G.238.244; 4.G.239.228; 4.G.239.229; 4.G.239.230;4.G.239.231; 4.G.239.236; 4.G.239.237; 4.G.239.238; 4.G.239.239;4.G.239.154; 4.G.239.157; 4.G.239.166; 4.G.239.169; 4.G.239.172;4.G.239.175; 4.G.239.240; 4.G.239.244; 4.G.154.228; 4.G.154.229;4.G.154.230; 4.G.154.231; 4.G.154.236; 4.G.154.237; 4.G.154.238;4.G.154.239; 4.G.154.154; 4.G.154.157; 4.G.154.166; 4.G.154.169;4.G.154.172; 4.G.154.175; 4.G.154.240; 4.G.154.244; 4.G.157.228;4.G.157.229; 4.G.157.230; 4.G.157.231; 4.G.157.236; 4.G.157.237;4.G.157.238; 4.G.157.239; 4.G.157.154; 4.G.157.157; 4.G.157.166;4.G.157.169; 4.G.157.172; 4.G.157.175; 4.G.157.240; 4.G.157.244;4.G.166.228; 4.G.166.229; 4.G.166.230; 4.G.166.231; 4.G.166.236;4.G.166.237; 4.G.166.238; 4.G.166.239; 4.G.166.154; 4.G.166.157;4.G.166.166; 4.G.166.169; 4.G.166.172; 4.G.166.175; 4.G.166.240;4.G.166.244; 4.G.169.228; 4.G.169.229; 4.G.169.230; 4.G.169.231;4.G.169.236; 4.G.169.237; 4.G.169.238; 4.G.169.239; 4.G.169.154;4.G.169.157; 4.G.169.166; 4.G.169.169; 4.G.169.172; 4.G.169.175;4.G.169.240; 4.G.169.244; 4.G.172.228; 4.G.172.229; 4.G.172.230;4.G.172.231; 4.G.172.236; 4.G.172.237; 4.G.172.238; 4.G.172.239;4.G.172.154; 4.G.172.157; 4.G.172.166; 4.G.172.169; 4.G.172.172;4.G.172.175; 4.G.172.240; 4.G.172.244; 4.G.175.228; 4.G.175.229;4.G.175.230; 4.G.175.231; 4.G.175.236; 4.G.175.237; 4.G.175.238;4.G.175.239; 4.G.175.154; 4.G.175.157; 4.G.175.166; 4.G.175.169;4.G.175.172; 4.G.175.175; 4.G.175.240; 4.G.175.244; 4.G.240.228;4.G.240.229; 4.G.240.230; 4.G.240.231; 4.G.240.236; 4.G.240.237;4.G.240.238; 4.G.240.239; 4.G.240.154; 4.G.240.157; 4.G.240.166;4.G.240.169; 4.G.240.172; 4.G.240.175; 4.G.240.240; 4.G.240.244;4.G.244.228; 4.G.244.229; 4.G.244.230; 4.G.244.231; 4.G.244.236;4.G.244.237; 4.G.244.238; 4.G.244.239; 4.G.244.154; 4.G.244.157;4.G.244.166; 4.G.244.169; 4.G.244.172; 4.G.244.175; 4.G.244.240;4.G.244.244; Prodrugs of 4.I 4.I.228.228; 4.I.228.229; 4.I.228.230;4.I.228.231; 4.I.228.236; 4.I.228.237; 4.I.228.238; 4.I.228.239;4.I.228.154; 4.I.228.157; 4.I.228.166; 4.I.228.169; 4.I.228.172;4.I.228.175; 4.I.228.240; 4.I.228.244; 4.I.229.228; 4.I.229.229;4.I.229.230; 4.I.229.231; 4.I.229.236; 4.I.229.237; 4.I.229.238;4.I.229.239; 4.I.229.154; 4.I.229.157; 4.I.229.166; 4.I.229.169;4.I.229.172; 4.I.229.175; 4.I.229.240; 4.I.229.244; 4.I.230.228;4.I.230.229; 4.I.230.230; 4.I.230.231; 4.I.230.236; 4.I.230.237;4.I.230.238; 4.I.230.239; 4.I.230.154; 4.I.230.157; 4.I.230.166;4.I.230.169; 4.I.230.172; 4.I.230.175; 4.I.230.240; 4.I.230.244;4.I.231.228; 4.I.231.229; 4.I.231.230; 4.I.231.231; 4.I.231.236;4.I.231.237; 4.I.231.238; 4.I.231.239; 4.I.231.154; 4.I.231.157;4.I.231.166; 4.I.231.169; 4.I.231.172; 4.I.231.175; 4.I.231.240;4.I.231.244; 4.I.236.228; 4.I.236.229; 4.I.236.230; 4.I.236.231;4.I.236.236; 4.I.236.237; 4.I.236.238; 4.I.236.239; 4.I.236.154;4.I.236.157; 4.I.236.166; 4.I.236.169; 4.I.236.172; 4.I.236.175;4.I.236.240; 4.I.236.244; 4.I.237.228; 4.I.237.229; 4.I.237.230;4.I.237.231; 4.I.237.236; 4.I.237.237; 4.I.237.238; 4.I.237.239;4.I.237.154; 4.I.237.157; 4.I.237.166; 4.I.237.169; 4.I.237.172;4.I.237.175; 4.I.237.240; 4.I.237.244; 4.I.238.228; 4.I.238.229;4.I.238.230; 4.I.238.231; 4.I.238.236; 4.I.238.237; 4.I.238.238;4.I.238.239; 4.I.238.154; 4.I.238.157; 4.I.238.166; 4.I.238.169;4.I.238.172; 4.I.238.175; 4.I.238.240; 4.I.238.244; 4.I.239.228;4.I.239.229; 4.I.239.230; 4.I.239.231; 4.I.239.236; 4.I.239.237;4.I.239.238; 4.I.239.239; 4.I.239.154; 4.I.239.157; 4.I.239.166;4.I.239.169; 4.I.239.172; 4.I.239.175; 4.I.239.240; 4.I.239.244;4.I.154.228; 4.I.154.229; 4.I.154.230; 4.I.154.231; 4.I.154.236;4.I.154.237; 4.I.154.238; 4.I.154.239; 4.I.154.154; 4.I.154.157;4.I.154.166; 4.I.154.169; 4.I.154.172; 4.I.154.175; 4.I.154.240;4.I.154.244; 4.I.157.228; 4.I.157.229; 4.I.157.230; 4.I.157.231;4.I.157.236; 4.I.157.237; 4.I.157.238; 4.I.157.239; 4.I.157.154;4.I.157.157; 4.I.157.166; 4.I.157.169; 4.I.157.172; 4.I.157.175;4.I.157.240; 4.I.157.244; 4.I.166.228; 4.I.166.229; 4.I.166.230;4.I.166.231; 4.I.166.236; 4.I.166.237; 4.I.166.238; 4.I.166.239;4.I.166.154; 4.I.166.157; 4.I.166.166; 4.I.166.169; 4.I.166.172;4.I.166.175; 4.I.166.240; 4.I.166.244; 4.I.169.228; 4.I.169.229;4.I.169.230; 4.I.169.231; 4.I.169.236; 4.I.169.237; 4.I.169.238;4.I.169.239; 4.I.169.154; 4.I.169.157; 4.I.169.166; 4.I.169.169;4.I.169.172; 4.I.169.175; 4.I.169.240; 4.I.169.244; 4.I.172.228;4.I.172.229; 4.I.172.230; 4.I.172.231; 4.I.172.236; 4.I.172.237;4.I.172.238; 4.I.172.239; 4.I.172.154; 4.I.172.157; 4.I.172.166;4.I.172.169; 4.I.172.172; 4.I.172.175; 4.I.172.240; 4.I.172.244;4.I.175.228; 4.I.175.229; 4.I.175.230; 4.I.175.231; 4.I.175.236;4.I.175.237; 4.I.175.238; 4.I.175.239; 4.I.175.154; 4.I.175.157;4.I.175.166; 4.I.175.169; 4.I.175.172; 4.I.175.175; 4.I.175.240;4.I.175.244; 4.I.240.228; 4.I.240.229; 4.I.240.230; 4.I.240.231;4.I.240.236; 4.I.240.237; 4.I.240.238; 4.I.240.239; 4.I.240.154;4.I.240.157; 4.I.240.166; 4.I.240.169; 4.I.240.172; 4.I.240.175;4.I.240.240; 4.I.240.244; 4.I.244.228; 4.I.244.229; 4.I.244.230;4.I.244.231; 4.I.244.236; 4.I.244.237; 4.I.244.238; 4.I.244.239;4.I.244.154; 4.I.244.157; 4.I.244.166; 4.I.244.169; 4.I.244.172;4.I.244.175; 4.I.244.240; 4.I.244.244; Prodrugs of 4.J 4.J.228.228;4.J.228.229; 4.J.228.230; 4.J.228.231; 4.J.228.236; 4.J.228.237;4.J.228.238; 4.J.228.239; 4.J.228.154; 4.J.228.157; 4.J.228.166;4.J.228.169; 4.J.228.172; 4.J.228.175; 4.J.228.240; 4.J.228.244;4.J.229.228; 4.J.229.229; 4.J.229.230; 4.J.229.231; 4.J.229.236;4.J.229.237; 4.J.229.238; 4.J.229.239; 4.J.229.154; 4.J.229.157;4.J.229.166; 4.J.229.169; 4.J.229.172; 4.J.229.175; 4.J.229.240;4.J.229.244; 4.J.230.228; 4.J.230.229; 4.J.230.230; 4.J.230.231;4.J.230.236; 4.J.230.237; 4.J.230.238; 4.J.230.239; 4.J.230.154;4.J.230.157; 4.J.230.166; 4.J.230.169; 4.J.230.172; 4.J.230.175;4.J.230.240; 4.J.230.244; 4.J.231.228; 4.J.231.229; 4.J.231.230;4.J.231.231; 4.J.231.236; 4.J.231.237; 4.J.231.238; 4.J.231.239;4.J.231.154; 4.J.231.157; 4.J.231.166; 4.J.231.169; 4.J.231.172;4.J.231.175; 4.J.231.240; 4.J.231.244; 4.J.236.228; 4.J.236.229;4.J.236.230; 4.J.236.231; 4.J.236.236; 4.J.236.237; 4.J.236.238;4.J.236.239; 4.J.236.154; 4.J.236.157; 4.J.236.166; 4.J.236.169;4.J.236.172; 4.J.236.175; 4.J.236.240; 4.J.236.244; 4.J.237.228;4.J.237.229; 4.J.237.230; 4.J.237.231; 4.J.237.236; 4.J.237.237;4.J.237.238; 4.J.237.239; 4.J.237.154; 4.J.237.157; 4.J.237.166;4.J.237.169; 4.J.237.172; 4.J.237.175; 4.J.237.240; 4.J.237.244;4.J.238.228; 4.J.238.229; 4.J.238.230; 4.J.238.231; 4.J.238.236;4.J.238.237; 4.J.238.238; 4.J.238.239; 4.J.238.154; 4.J.238.157;4.J.238.166; 4.J.238.169; 4.J.238.172; 4.J.238.175; 4.J.238.240;4.J.238.244; 4.J.239.228; 4.J.239.229; 4.J.239.230; 4.J.239.231;4.J.239.236; 4.J.239.237; 4.J.239.238; 4.J.239.239; 4.J.239.154;4.J.239.157; 4.J.239.166; 4.J.239.169; 4.J.239.172; 4.J.239.175;4.J.239.240; 4.J.239.244; 4.J.154.228; 4.J.154.229; 4.J.154.230;4.J.154.231; 4.J.154.236; 4.J.154.237; 4.J.154.238; 4.J.154.239;4.J.154.154; 4.J.154.157; 4.J.154.166; 4.J.154.169; 4.J.154.172;4.J.154.175; 4.J.154.240; 4.J.154.244; 4.J.157.228; 4.J.157.229;4.J.157.230; 4.J.157.231; 4.J.157.236; 4.J.157.237; 4.J.157.238;4.J.157.239; 4.J.157.154; 4.J.157.157; 4.J.157.166; 4.J.157.169;4.J.157.172; 4.J.157.175; 4.J.157.240; 4.J.157.244; 4.J.166.228;4.J.166.229; 4.J.166.230; 4.J.166.231; 4.J.166.236; 4.J.166.237;4.J.166.238; 4.J.166.239; 4.J.166.154; 4.J.166.157; 4.J.166.166;4.J.166.169; 4.J.166.172; 4.J.166.175; 4.J.166.240; 4.J.166.244;4.J.169.228; 4.J.169.229; 4.J.169.230; 4.J.169.231; 4.J.169.236;4.J.169.237; 4.J.169.238; 4.J.169.239; 4.J.169.154; 4.J.169.157;4.J.169.166; 4.J.169.169; 4.J.169.172; 4.J.169.175; 4.J.169.240;4.J.169.244; 4.J.172.228; 4.J.172.229; 4.J.172.230; 4.J.172.231;4.J.172.236; 4.J.172.237; 4.J.172.238; 4.J.172.239; 4.J.172.154;4.J.172.157; 4.J.172.166; 4.J.172.169; 4.J.172.172; 4.J.172.175;4.J.172.240; 4.J.172.244; 4.J.175.228; 4.J.175.229; 4.J.175.230;4.J.175.231; 4.J.175.236; 4.J.175.237; 4.J.175.238; 4.J.175.239;4.J.175.154; 4.J.175.157; 4.J.175.166; 4.J.175.169; 4.J.175.172;4.J.175.175; 4.J.175.240; 4.J.175.244; 4.J.240.228; 4.J.240.229;4.J.240.230; 4.J.240.231; 4.J.240.236; 4.J.240.237; 4.J.240.238;4.J.240.239; 4.J.240.154; 4.J.240.157; 4.J.240.166; 4.J.240.169;4.J.240.172; 4.J.240.175; 4.J.240.240; 4.J.240.244; 4.J.244.228;4.J.244.229; 4.J.244.230; 4.J.244.231; 4.J.244.236; 4.J.244.237;4.J.244.238; 4.J.244.239; 4.J.244.154; 4.J.244.157; 4.J.244.166;4.J.244.169; 4.J.244.172; 4.J.244.175; 4.J.244.240; 4.J.244.244;Prodrugs of 4.L 4.L.228.228; 4.L.228.229; 4.L.228.230; 4.L.228.231;4.L.228.236; 4.L.228.237; 4.L.228.238; 4.L.228.239; 4.L.228.154;4.L.228.157; 4.L.228.166; 4.L.228.169; 4.L.228.172; 4.L.228.175;4.L.228.240; 4.L.228.244; 4.L.229.228; 4.L.229.229; 4.L.229.230;4.L.229.231; 4.L.229.236; 4.L.229.237; 4.L.229.238; 4.L.229.239;4.L.229.154; 4.L.229.157; 4.L.229.166; 4.L.229.169; 4.L.229.172;4.L.229.175; 4.L.229.240; 4.L.229.244; 4.L.230.228; 4.L.230.229;4.L.230.230; 4.L.230.231; 4.L.230.236; 4.L.230.237; 4.L.230.238;4.L.230.239; 4.L.230.154; 4.L.230.157; 4.L.230.166; 4.L.230.169;4.L.230.172; 4.L.230.175; 4.L.230.240; 4.L.230.244; 4.L.231.228;4.L.231.229; 4.L.231.230; 4.L.231.231; 4.L.231.236; 4.L.231.237;4.L.231.238; 4.L.231.239; 4.L.231.154; 4.L.231.157; 4.L.231.166;4.L.231.169; 4.L.231.172; 4.L.231.175; 4.L.231.240; 4.L.231.244;4.L.236.228; 4.L.236.229; 4.L.236.230; 4.L.236.231; 4.L.236.236;4.L.236.237; 4.L.236.238; 4.L.236.239; 4.L.236.154; 4.L.236.157;4.L.236.166; 4.L.236.169; 4.L.236.172; 4.L.236.175; 4.L.236.240;4.L.236.244; 4.L.237.228; 4.L.237.229; 4.L.237.230; 4.L.237.231;4.L.237.236; 4.L.237.237; 4.L.237.238; 4.L.237.239; 4.L.237.154;4.L.237.157; 4.L.237.166; 4.L.237.169; 4.L.237.172; 4.L.237.175;4.L.237.240; 4.L.237.244; 4.L.238.228; 4.L.238.229; 4.L.238.230;4.L.238.231; 4.L.238.236; 4.L.238.237; 4.L.238.238; 4.L.238.239;4.L.238.154; 4.L.238.157; 4.L.238.166; 4.L.238.169; 4.L.238.172;4.L.238.175; 4.L.238.240; 4.L.238.244; 4.L.239.228; 4.L.239.229;4.L.239.230; 4.L.239.231; 4.L.239.236; 4.L.239.237; 4.L.239.238;4.L.239.239; 4.L.239.154; 4.L.239.157; 4.L.239.166; 4.L.239.169;4.L.239.172; 4.L.239.175; 4.L.239.240; 4.L.239.244; 4.L.154.228;4.L.154.229; 4.L.154.230; 4.L.154.231; 4.L.154.236; 4.L.154.237;4.L.154.238; 4.L.154.239; 4.L.154.154; 4.L.154.157; 4.L.154.166;4.L.154.169; 4.L.154.172; 4.L.154.175; 4.L.154.240; 4.L.154.244;4.L.157.228; 4.L.157.229; 4.L.157.230; 4.L.157.231; 4.L.157.236;4.L.157.237; 4.L.157.238; 4.L.157.239; 4.L.157.154; 4.L.157.157;4.L.157.166; 4.L.157.169; 4.L.157.172; 4.L.157.175; 4.L.157.240;4.L.157.244; 4.L.166.228; 4.L.166.229; 4.L.166.230; 4.L.166.231;4.L.166.236; 4.L.166.237; 4.L.166.238; 4.L.166.239; 4.L.166.154;4.L.166.157; 4.L.166.166; 4.L.166.169; 4.L.166.172; 4.L.166.175;4.L.166.240; 4.L.166.244; 4.L.169.228; 4.L.169.229; 4.L.169.230;4.L.169.231; 4.L.169.236; 4.L.169.237; 4.L.169.238; 4.L.169.239;4.L.169.154; 4.L.169.157; 4.L.169.166; 4.L.169.169; 4.L.169.172;4.L.169.175; 4.L.169.240; 4.L.169.244; 4.L.172.228; 4.L.172.229;4.L.172.230; 4.L.172.231; 4.L.172.236; 4.L.172.237; 4.L.172.238;4.L.172.239; 4.L.172.154; 4.L.172.157; 4.L.172.166; 4.L.172.169;4.L.172.172; 4.L.172.175; 4.L.172.240; 4.L.172.244; 4.L.175.228;4.L.175.229; 4.L.175.230; 4.L.175.231; 4.L.175.236; 4.L.175.237;4.L.175.238; 4.L.175.239; 4.L.175.154; 4.L.175.157; 4.L.175.166;4.L.175.169; 4.L.175.172; 4.L.175.175; 4.L.175.240; 4.L.175.244;4.L.240.228; 4.L.240.229; 4.L.240.230; 4.L.240.231; 4.L.240.236;4.L.240.237; 4.L.240.238; 4.L.240.239; 4.L.240.154; 4.L.240.157;4.L.240.166; 4.L.240.169; 4.L.240.172; 4.L.240.175; 4.L.240.240;4.L.240.244; 4.L.244.228; 4.L.244.229; 4.L.244.230; 4.L.244.231;4.L.244.236; 4.L.244.237; 4.L.244.238; 4.L.244.239; 4.L.244.154;4.L.244.157; 4.L.244.166; 4.L.244.169; 4.L.244.172; 4.L.244.175;4.L.244.240; 4.L.244.244; Prodrugs of 4.O 4.O.228.228; 4.O.228.229;4.O.228.230; 4.O.228.231; 4.O.228.236; 4.O.228.237; 4.O.228.238;4.O.228.239; 4.O.228.154; 4.O.228.157; 4.O.228.166; 4.O.228.169;4.O.228.172; 4.O.228.175; 4.O.228.240; 4.O.228.244; 4.O.229.228;4.O.229.229; 4.O.229.230; 4.O.229.231; 4.O.229.236; 4.O.229.237;4.O.229.238; 4.O.229.239; 4.O.229.154; 4.O.229.157; 4.O.229.166;4.O.229.169; 4.O.229.172; 4.O.229.175; 4.O.229.240; 4.O.229.244;4.O.230.228; 4.O.230.229; 4.O.230.230; 4.O.230.231; 4.O.230.236;4.O.230.237; 4.O.230.238; 4.O.230.239; 4.O.230.154; 4.O.230.157;4.O.230.166; 4.O.230.169; 4.O.230.172; 4.O.230.175; 4.O.230.240;4.O.230.244; 4.O.231.228; 4.O.231.229; 4.O.231.230; 4.O.231.231;4.O.231.236; 4.O.231.237; 4.O.231.238; 4.O.231.239; 4.O.231.154;4.O.231.157; 4.O.231.166; 4.O.231.169; 4.O.231.172; 4.O.231.175;4.O.231.240; 4.O.231.244; 4.O.236.228; 4.O.236.229; 4.O.236.230;4.O.236.231; 4.O.236.236; 4.O.236.237; 4.O.236.238; 4.O.236.239;4.O.236.154; 4.O.236.157; 4.O.236.166; 4.O.236.169; 4.O.236.172;4.O.236.175; 4.O.236.240; 4.O.236.244; 4.O.237.228; 4.O.237.229;4.O.237.230; 4.O.237.231; 4.O.237.236; 4.O.237.237; 4.O.237.238;4.O.237.239; 4.O.237.154; 4.O.237.157; 4.O.237.166; 4.O.237.169;4.O.237.172; 4.O.237.175; 4.O.237.240; 4.O.237.244; 4.O.238.228;4.O.238.229; 4.O.238.230; 4.O.238.231; 4.O.238.236; 4.O.238.237;4.O.238.238; 4.O.238.239; 4.O.238.154; 4.O.238.157; 4.O.238.166;4.O.238.169; 4.O.238.172; 4.O.238.175; 4.O.238.240; 4.O.238.244;4.O.239.228; 4.O.239.229; 4.O.239.230; 4.O.239.231; 4.O.239.236;4.O.239.237; 4.O.239.238; 4.O.239.239; 4.O.239.154; 4.O.239.157;4.O.239.166; 4.O.239.169; 4.O.239.172; 4.O.239.175; 4.O.239.240;4.O.239.244; 4.O.154.228; 4.O.154.229; 4.O.154.230; 4.O.154.231;4.O.154.236; 4.O.154.237; 4.O.154.238; 4.O.154.239; 4.O.154.154;4.O.154.157; 4.O.154.166; 4.O.154.169; 4.O.154.172; 4.O.154.175;4.O.154.240; 4.O.154.244; 4.O.157.228; 4.O.157.229; 4.O.157.230;4.O.157.231; 4.O.157.236; 4.O.157.237; 4.O.157.238; 4.O.157.239;4.O.157.154; 4.O.157.157; 4.O.157.166; 4.O.157.169; 4.O.157.172;4.O.157.175; 4.O.157.240; 4.O.157.244; 4.O.166.228; 4.O.166.229;4.O.166.230; 4.O.166.231; 4.O.166.236; 4.O.166.237; 4.O.166.238;4.O.166.239; 4.O.166.154; 4.O.166.157; 4.O.166.166; 4.O.166.169;4.O.166.172; 4.O.166.175; 4.O.166.240; 4.O.166.244; 4.O.169.228;4.O.169.229; 4.O.169.230; 4.O.169.231; 4.O.169.236; 4.O.169.237;4.O.169.238; 4.O.169.239; 4.O.169.154; 4.O.169.157; 4.O.169.166;4.O.169.169; 4.O.169.172; 4.O.169.175; 4.O.169.240; 4.O.169.244;4.O.172.228; 4.O.172.229; 4.O.172.230; 4.O.172.231; 4.O.172.236;4.O.172.237; 4.O.172.238; 4.O.172.239; 4.O.172.154; 4.O.172.157;4.O.172.166; 4.O.172.169; 4.O.172.172; 4.O.172.175; 4.O.172.240;4.O.172.244; 4.O.175.228; 4.O.175.229; 4.O.175.230; 4.O.175.231;4.O.175.236; 4.O.175.237; 4.O.175.238; 4.O.175.239; 4.O.175.154;4.O.175.157; 4.O.175.166; 4.O.175.169; 4.O.175.172; 4.O.175.175;4.O.175.240; 4.O.175.244; 4.O.240.228; 4.O.240.229; 4.O.240.230;4.O.240.231; 4.O.240.236; 4.O.240.237; 4.O.240.238; 4.O.240.239;4.O.240.154; 4.O.240.157; 4.O.240.166; 4.O.240.169; 4.O.240.172;4.O.240.175; 4.O.240.240; 4.O.240.244; 4.O.244.228; 4.O.244.229;4.O.244.230; 4.O.244.231; 4.O.244.236; 4.O.244.237; 4.O.244.238;4.O.244.239; 4.O.244.154; 4.O.244.157; 4.O.244.166; 4.O.244.169;4.O.244.172; 4.O.244.175; 4.O.244.240; 4.O.244.244; Prodrugs of 4.P4.P.228.228; 4.P.228.229; 4.P.228.230; 4.P.228.231; 4.P.228.236;4.P.228.237; 4.P.228.238; 4.P.228.239; 4.P.228.154; 4.P.228.157;4.P.228.166; 4.P.228.169; 4.P.228.172; 4.P.228.175; 4.P.228.240;4.P.228.244; 4.P.229.228; 4.P.229.229; 4.P.229.230; 4.P.229.231;4.P.229.236; 4.P.229.237; 4.P.229.238; 4.P.229.239; 4.P.229.154;4.P.229.157; 4.P.229.166; 4.P.229.169; 4.P.229.172; 4.P.229.175;4.P.229.240; 4.P.229.244; 4.P.230.228; 4.P.230.229; 4.P.230.230;4.P.230.231; 4.P.230.236; 4.P.230.237; 4.P.230.238; 4.P.230.239;4.P.230.154; 4.P.230.157; 4.P.230.166; 4.P.230.169; 4.P.230.172;4.P.230.175; 4.P.230.240; 4.P.230.244; 4.P.231.228; 4.P.231.229;4.P.231.230; 4.P.231.231; 4.P.231.236; 4.P.231.237; 4.P.231.238;4.P.231.239; 4.P.231.154; 4.P.231.157; 4.P.231.166; 4.P.231.169;4.P.231.172; 4.P.231.175; 4.P.231.240; 4.P.231.244; 4.P.236.228;4.P.236.229; 4.P.236.230; 4.P.236.231; 4.P.236.236; 4.P.236.237;4.P.236.238; 4.P.236.239; 4.P.236.154; 4.P.236.157; 4.P.236.166;4.P.236.169; 4.P.236.172; 4.P.236.175; 4.P.236.240; 4.P.236.244;4.P.237.228; 4.P.237.229; 4.P.237.230; 4.P.237.231; 4.P.237.236;4.P.237.237; 4.P.237.238; 4.P.237.239; 4.P.237.154; 4.P.237.157;4.P.237.166; 4.P.237.169; 4.P.237.172; 4.P.237.175; 4.P.237.240;4.P.237.244; 4.P.238.228; 4.P.238.229; 4.P.238.230; 4.P.238.231;4.P.238.236; 4.P.238.237; 4.P.238.238; 4.P.238.239; 4.P.238.154;4.P.238.157; 4.P.238.166; 4.P.238.169; 4.P.238.172; 4.P.238.175;4.P.238.240; 4.P.238.244; 4.P.239.228; 4.P.239.229; 4.P.239.230;4.P.239.231; 4.P.239.236; 4.P.239.237; 4.P.239.238; 4.P.239.239;4.P.239.154; 4.P.239.157; 4.P.239.166; 4.P.239.169; 4.P.239.172;4.P.239.175; 4.P.239.240; 4.P.239.244; 4.P.154.228; 4.P.154.229;4.P.154.230; 4.P.154.231; 4.P.154.236; 4.P.154.237; 4.P.154.238;4.P.154.239; 4.P.154.154; 4.P.154.157; 4.P.154.166; 4.P.154.169;4.P.154.172; 4.P.154.175; 4.P.154.240; 4.P.154.244; 4.P.157.228;4.P.157.229; 4.P.157.230; 4.P.157.231; 4.P.157.236; 4.P.157.237;4.P.157.238; 4.P.157.239; 4.P.157.154; 4.P.157.157; 4.P.157.166;4.P.157.169; 4.P.157.172; 4.P.157.175; 4.P.157.240; 4.P.157.244;4.P.166.228; 4.P.166.229; 4.P.166.230; 4.P.166.231; 4.P.166.236;4.P.166.237; 4.P.166.238; 4.P.166.239; 4.P.166.154; 4.P.166.157;4.P.166.166; 4.P.166.169; 4.P.166.172; 4.P.166.175; 4.P.166.240;4.P.166.244; 4.P.169.228; 4.P.169.229; 4.P.169.230; 4.P.169.231;4.P.169.236; 4.P.169.237; 4.P.169.238; 4.P.169.239; 4.P.169.154;4.P.169.157; 4.P.169.166; 4.P.169.169; 4.P.169.172; 4.P.169.175;4.P.169.240; 4.P.169.244; 4.P.172.228; 4.P.172.229; 4.P.172.230;4.P.172.231; 4.P.172.236; 4.P.172.237; 4.P.172.238; 4.P.172.239;4.P.172.154; 4.P.172.157; 4.P.172.166; 4.P.172.169; 4.P.172.172;4.P.172.175; 4.P.172.240; 4.P.172.244; 4.P.175.228; 4.P.175.229;4.P.175.230; 4.P.175.231; 4.P.175.236; 4.P.175.237; 4.P.175.238;4.P.175.239; 4.P.175.154; 4.P.175.157; 4.P.175.166; 4.P.175.169;4.P.175.172; 4.P.175.175; 4.P.175.240; 4.P.175.244; 4.P.240.228;4.P.240.229; 4.P.240.230; 4.P.240.231; 4.P.240.236; 4.P.240.237;4.P.240.238; 4.P.240.239; 4.P.240.154; 4.P.240.157; 4.P.240.166;4.P.240.169; 4.P.240.172; 4.P.240.175; 4.P.240.240; 4.P.240.244;4.P.244.228; 4.P.244.229; 4.P.244.230; 4.P.244.231; 4.P.244.236;4.P.244.237; 4.P.244.238; 4.P.244.239; 4.P.244.154; 4.P.244.157;4.P.244.166; 4.P.244.169; 4.P.244.172; 4.P.244.175; 4.P.244.240;4.P.244.244; Prodrugs of 4.U 4.U.228.228; 4.U.228.229; 4.U.228.230;4.U.228.231; 4.U.228.236; 4.U.228.237; 4.U.228.238; 4.U.228.239;4.U.228.154; 4.U.228.157; 4.U.228.166; 4.U.228.169; 4.U.228.172;4.U.228.175; 4.U.228.240; 4.U.228.244; 4.U.229.228; 4.U.229.229;4.U.229.230; 4.U.229.231; 4.U.229.236; 4.U.229.237; 4.U.229.238;4.U.229.239; 4.U.229.154; 4.U.229.157; 4.U.229.166; 4.U.229.169;4.U.229.172; 4.U.229.175; 4.U.229.240; 4.U.229.244; 4.U.230.228;4.U.230.229; 4.U.230.230; 4.U.230.231; 4.U.230.236; 4.U.230.237;4.U.230.238; 4.U.230.239; 4.U.230.154; 4.U.230.157; 4.U.230.166;4.U.230.169; 4.U.230.172; 4.U.230.175; 4.U.230.240; 4.U.230.244;4.U.231.228; 4.U.231.229; 4.U.231.230; 4.U.231.231; 4.U.231.236;4.U.231.237; 4.U.231.238; 4.U.231.239; 4.U.231.154; 4.U.231.157;4.U.231.166; 4.U.231.169; 4.U.231.172; 4.U.231.175; 4.U.231.240;4.U.231.244; 4.U.236.228; 4.U.236.229; 4.U.236.230; 4.U.236.231;4.U.236.236; 4.U.236.237; 4.U.236.238; 4.U.236.239; 4.U.236.154;4.U.236.157; 4.U.236.166; 4.U.236.169; 4.U.236.172; 4.U.236.175;4.U.236.240; 4.U.236.244; 4.U.237.228; 4.U.237.229; 4.U.237.230;4.U.237.231; 4.U.237.236; 4.U.237.237; 4.U.237.238; 4.U.237.239;4.U.237.154; 4.U.237.157; 4.U.237.166; 4.U.237.169; 4.U.237.172;4.U.237.175; 4.U.237.240; 4.U.237.244; 4.U.238.228; 4.U.238.229;4.U.238.230; 4.U.238.231; 4.U.238.236; 4.U.238.237; 4.U.238.238;4.U.238.239; 4.U.238.154; 4.U.238.157; 4.U.238.166; 4.U.238.169;4.U.238.172; 4.U.238.175; 4.U.238.240; 4.U.238.244; 4.U.239.228;4.U.239.229; 4.U.239.230; 4.U.239.231; 4.U.239.236; 4.U.239.237;4.U.239.238; 4.U.239.239; 4.U.239.154; 4.U.239.157; 4.U.239.166;4.U.239.169; 4.U.239.172; 4.U.239.175; 4.U.239.240; 4.U.239.244;4.U.154.228; 4.U.154.229; 4.U.154.230; 4.U.154.231; 4.U.154.236;4.U.154.237; 4.U.154.238; 4.U.154.239; 4.U.154.154; 4.U.154.157;4.U.154.166; 4.U.154.169; 4.U.154.172; 4.U.154.175; 4.U.154.240;4.U.154.244; 4.U.157.228; 4.U.157.229; 4.U.157.230; 4.U.157.231;4.U.157.236; 4.U.157.237; 4.U.157.238; 4.U.157.239; 4.U.157.154;4.U.157.157; 4.U.157.166; 4.U.157.169; 4.U.157.172; 4.U.157.175;4.U.157.240; 4.U.157.244; 4.U.166.228; 4.U.166.229; 4.U.166.230;4.U.166.231; 4.U.166.236; 4.U.166.237; 4.U.166.238; 4.U.166.239;4.U.166.154; 4.U.166.157; 4.U.166.166; 4.U.166.169; 4.U.166.172;4.U.166.175; 4.U.166.240; 4.U.166.244; 4.U.169.228; 4.U.169.229;4.U.169.230; 4.U.169.231; 4.U.169.236; 4.U.169.237; 4.U.169.238;4.U.169.239; 4.U.169.154; 4.U.169.157; 4.U.169.166; 4.U.169.169;4.U.169.172; 4.U.169.175; 4.U.169.240; 4.U.169.244; 4.U.172.228;4.U.172.229; 4.U.172.230; 4.U.172.231; 4.U.172.236; 4.U.172.237;4.U.172.238; 4.U.172.239; 4.U.172.154; 4.U.172.157; 4.U.172.166;4.U.172.169; 4.U.172.172; 4.U.172.175; 4.U.172.240; 4.U.172.244;4.U.175.228; 4.U.175.229; 4.U.175.230; 4.U.175.231; 4.U.175.236;4.U.175.237; 4.U.175.238; 4.U.175.239; 4.U.175.154; 4.U.175.157;4.U.175.166; 4.U.175.169; 4.U.175.172; 4.U.175.175; 4.U.175.240;4.U.175.244; 4.U.240.228; 4.U.240.229; 4.U.240.230; 4.U.240.231;4.U.240.236; 4.U.240.237; 4.U.240.238; 4.U.240.239; 4.U.240.154;4.U.240.157; 4.U.240.166; 4.U.240.169; 4.U.240.172; 4.U.240.175;4.U.240.240; 4.U.240.244; 4.U.244.228; 4.U.244.229; 4.U.244.230;4.U.244.231; 4.U.244.236; 4.U.244.237; 4.U.244.238; 4.U.244.239;4.U.244.154; 4.U.244.157; 4.U.244.166; 4.U.244.169; 4.U.244.172;4.U.244.175; 4.U.244.240; 4.U.244.244; Prodrugs of 4.W 4.W.228.228;4.W.228.229; 4.W.228.230; 4.W.228.231; 4.W.228.236; 4.W.228.237;4.W.228.238; 4.W.228.239; 4.W.228.154; 4.W.228.157; 4.W.228.166;4.W.228.169; 4.W.228.172; 4.W.228.175; 4.W.228.240; 4.W.228.244;4.W.229.228; 4.W.229.229; 4.W.229.230; 4.W.229.231; 4.W.229.236;4.W.229.237; 4.W.229.238; 4.W.229.239; 4.W.229.154; 4.W.229.157;4.W.229.166; 4.W.229.169; 4.W.229.172; 4.W.229.175; 4.W.229.240;4.W.229.244; 4.W.230.228; 4.W.230.229; 4.W.230.230; 4.W.230.231;4.W.230.236; 4.W.230.237; 4.W.230.238; 4.W.230.239; 4.W.230.154;4.W.230.157; 4.W.230.166; 4.W.230.169; 4.W.230.172; 4.W.230.175;4.W.230.240; 4.W.230.244; 4.W.231.228; 4.W.231.229; 4.W.231.230;4.W.231.231; 4.W.231.236; 4.W.231.237; 4.W.231.238; 4.W.231.239;4.W.231.154; 4.W.231.157; 4.W.231.166; 4.W.231.169; 4.W.231.172;4.W.231.175; 4.W.231.240; 4.W.231.244; 4.W.236.228; 4.W.236.229;4.W.236.230; 4.W.236.231; 4.W.236.236; 4.W.236.237; 4.W.236.238;4.W.236.239; 4.W.236.154; 4.W.236.157; 4.W.236.166; 4.W.236.169;4.W.236.172; 4.W.236.175; 4.W.236.240; 4.W.236.244; 4.W.237.228;4.W.237.229; 4.W.237.230; 4.W.237.231; 4.W.237.236; 4.W.237.237;4.W.237.238; 4.W.237.239; 4.W.237.154; 4.W.237.157; 4.W.237.166;4.W.237.169; 4.W.237.172; 4.W.237.175; 4.W.237.240; 4.W.237.244;4.W.238.228; 4.W.238.229; 4.W.238.230; 4.W.238.231; 4.W.238.236;4.W.238.237; 4.W.238.238; 4.W.238.239; 4.W.238.154; 4.W.238.157;4.W.238.166; 4.W.238.169; 4.W.238.172; 4.W.238.175; 4.W.238.240;4.W.238.244; 4.W.239.228; 4.W.239.229; 4.W.239.230; 4.W.239.231;4.W.239.236; 4.W.239.237; 4.W.239.238; 4.W.239.239; 4.W.239.154;4.W.239.157; 4.W.239.166; 4.W.239.169; 4.W.239.172; 4.W.239.175;4.W.239.240; 4.W.239.244; 4.W.154.228; 4.W.154.229; 4.W.154.230;4.W.154.231; 4.W.154.236; 4.W.154.237; 4.W.154.238; 4.W.154.239;4.W.154.154; 4.W.154.157; 4.W.154.166; 4.W.154.169; 4.W.154.172;4.W.154.175; 4.W.154.240; 4.W.154.244; 4.W.157.228; 4.W.157.229;4.W.157.230; 4.W.157.231; 4.W.157.236; 4.W.157.237; 4.W.157.238;4.W.157.239; 4.W.157.154; 4.W.157.157; 4.W.157.166; 4.W.157.169;4.W.157.172; 4.W.157.175; 4.W.157.240; 4.W.157.244; 4.W.166.228;4.W.166.229; 4.W.166.230; 4.W.166.231; 4.W.166.236; 4.W.166.237;4.W.166.238; 4.W.166.239; 4.W.166.154; 4.W.166.157; 4.W.166.166;4.W.166.169; 4.W.166.172; 4.W.166.175; 4.W.166.240; 4.W.166.244;4.W.169.228; 4.W.169.229; 4.W.169.230; 4.W.169.231; 4.W.169.236;4.W.169.237; 4.W.169.238; 4.W.169.239; 4.W.169.154; 4.W.169.157;4.W.169.166; 4.W.169.169; 4.W.169.172; 4.W.169.175; 4.W.169.240;4.W.169.244; 4.W.172.228; 4.W.172.229; 4.W.172.230; 4.W.172.231;4.W.172.236; 4.W.172.237; 4.W.172.238; 4.W.172.239; 4.W.172.154;4.W.172.157; 4.W.172.166; 4.W.172.169; 4.W.172.172; 4.W.172.175;4.W.172.240; 4.W.172.244; 4.W.175.228; 4.W.175.229; 4.W.175.230;4.W.175.231; 4.W.175.236; 4.W.175.237; 4.W.175.238; 4.W.175.239;4.W.175.154; 4.W.175.157; 4.W.175.166; 4.W.175.169; 4.W.175.172;4.W.175.175; 4.W.175.240; 4.W.175.244; 4.W.240.228; 4.W.240.229;4.W.240.230; 4.W.240.231; 4.W.240.236; 4.W.240.237; 4.W.240.238;4.W.240.239; 4.W.240.154; 4.W.240.157; 4.W.240.166; 4.W.240.169;4.W.240.172; 4.W.240.175; 4.W.240.240; 4.W.240.244; 4.W.244.228;4.W.244.229; 4.W.244.230; 4.W.244.231; 4.W.244.236; 4.W.244.237;4.W.244.238; 4.W.244.239; 4.W.244.154; 4.W.244.157; 4.W.244.166;4.W.244.169; 4.W.244.172; 4.W.244.175; 4.W.244.240; 4.W.244.244;Prodrugs of 4.Y 4.Y.228.228; 4.Y.228.229; 4.Y.228.230; 4.Y.228.231;4.Y.228.236; 4.Y.228.237; 4.Y.228.238; 4.Y.228.239; 4.Y.228.154;4.Y.228.157; 4.Y.228.166; 4.Y.228.169; 4.Y.228.172; 4.Y.228.175;4.Y.228.240; 4.Y.228.244; 4.Y.229.228; 4.Y.229.229; 4.Y.229.230;4.Y.229.231; 4.Y.229.236; 4.Y.229.237; 4.Y.229.238; 4.Y.229.239;4.Y.229.154; 4.Y.229.157; 4.Y.229.166; 4.Y.229.169; 4.Y.229.172;4.Y.229.175; 4.Y.229.240; 4.Y.229.244; 4.Y.230.228; 4.Y.230.229;4.Y.230.230; 4.Y.230.231; 4.Y.230.236; 4.Y.230.237; 4.Y.230.238;4.Y.230.239; 4.Y.230.154; 4.Y.230.157; 4.Y.230.166; 4.Y.230.169;4.Y.230.172; 4.Y.230.175; 4.Y.230.240; 4.Y.230.244; 4.Y.231.228;4.Y.231.229; 4.Y.231.230; 4.Y.231.231; 4.Y.231.236; 4.Y.231.237;4.Y.231.238; 4.Y.231.239; 4.Y.231.154; 4.Y.231.157; 4.Y.231.166;4.Y.231.169; 4.Y.231.172; 4.Y.231.175; 4.Y.231.240; 4.Y.231.244;4.Y.236.228; 4.Y.236.229; 4.Y.236.230; 4.Y.236.231; 4.Y.236.236;4.Y.236.237; 4.Y.236.238; 4.Y.236.239; 4.Y.236.154; 4.Y.236.157;4.Y.236.166; 4.Y.236.169; 4.Y.236.172; 4.Y.236.175; 4.Y.236.240;4.Y.236.244; 4.Y.237.228; 4.Y.237.229; 4.Y.237.230; 4.Y.237.231;4.Y.237.236; 4.Y.237.237; 4.Y.237.238; 4.Y.237.239; 4.Y.237.154;4.Y.237.157; 4.Y.237.166; 4.Y.237.169; 4.Y.237.172; 4.Y.237.175;4.Y.237.240; 4.Y.237.244; 4.Y.238.228; 4.Y.238.229; 4.Y.238.230;4.Y.238.231; 4.Y.238.236; 4.Y.238.237; 4.Y.238.238; 4.Y.238.239;4.Y.238.154; 4.Y.238.157; 4.Y.238.166; 4.Y.238.169; 4.Y.238.172;4.Y.238.175; 4.Y.238.240; 4.Y.238.244; 4.Y.239.228; 4.Y.239.229;4.Y.239.230; 4.Y.239.231; 4.Y.239.236; 4.Y.239.237; 4.Y.239.238;4.Y.239.239; 4.Y.239.154; 4.Y.239.157; 4.Y.239.166; 4.Y.239.169;4.Y.239.172; 4.Y.239.175; 4.Y.239.240; 4.Y.239.244; 4.Y.154.228;4.Y.154.229; 4.Y.154.230; 4.Y.154.231; 4.Y.154.236; 4.Y.154.237;4.Y.154.238; 4.Y.154.239; 4.Y.154.154; 4.Y.154.157; 4.Y.154.166;4.Y.154.169; 4.Y.154.172; 4.Y.154.175; 4.Y.154.240; 4.Y.154.244;4.Y.157.228; 4.Y.157.229; 4.Y.157.230; 4.Y.157.231; 4.Y.157.236;4.Y.157.237; 4.Y.157.238; 4.Y.157.239; 4.Y.157.154; 4.Y.157.157;4.Y.157.166; 4.Y.157.169; 4.Y.157.172; 4.Y.157.175; 4.Y.157.240;4.Y.157.244; 4.Y.166.228; 4.Y.166.229; 4.Y.166.230; 4.Y.166.231;4.Y.166.236; 4.Y.166.237; 4.Y.166.238; 4.Y.166.239; 4.Y.166.154;4.Y.166.157; 4.Y.166.166; 4.Y.166.169; 4.Y.166.172; 4.Y.166.175;4.Y.166.240; 4.Y.166.244; 4.Y.169.228; 4.Y.169.229; 4.Y.169.230;4.Y.169.231; 4.Y.169.236; 4.Y.169.237; 4.Y.169.238; 4.Y.169.239;4.Y.169.154; 4.Y.169.157; 4.Y.169.166; 4.Y.169.169; 4.Y.169.172;4.Y.169.175; 4.Y.169.240; 4.Y.169.244; 4.Y.172.228; 4.Y.172.229;4.Y.172.230; 4.Y.172.231; 4.Y.172.236; 4.Y.172.237; 4.Y.172.238;4.Y.172.239; 4.Y.172.154; 4.Y.172.157; 4.Y.172.166; 4.Y.172.169;4.Y.172.172; 4.Y.172.175; 4.Y.172.240; 4.Y.172.244; 4.Y.175.228;4.Y.175.229; 4.Y.175.230; 4.Y.175.231; 4.Y.175.236; 4.Y.175.237;4.Y.175.238; 4.Y.175.239; 4.Y.175.154; 4.Y.175.157; 4.Y.175.166;4.Y.175.169; 4.Y.175.172; 4.Y.175.175; 4.Y.175.240; 4.Y.175.244;4.Y.240.228; 4.Y.240.229; 4.Y.240.230; 4.Y.240.231; 4.Y.240.236;4.Y.240.237; 4.Y.240.238; 4.Y.240.239; 4.Y.240.154; 4.Y.240.157;4.Y.240.166; 4.Y.240.169; 4.Y.240.172; 4.Y.240.175; 4.Y.240.240;4.Y.240.244; 4.Y.244.228; 4.Y.244.229; 4.Y.244.230; 4.Y.244.231;4.Y.244.236; 4.Y.244.237; 4.Y.244.238; 4.Y.244.239; 4.Y.244.154;4.Y.244.157; 4.Y.244.166; 4.Y.244.169; 4.Y.244.172; 4.Y.244.175;4.Y.244.240; 4.Y.244.244; Prodrugs of 5.B 5.B.228.228; 5.B.228.229;5.B.228.230; 5.B.228.231; 5.B.228.236; 5.B.228.237; 5.B.228.238;5.B.228.239; 5.B.228.154; 5.B.228.157; 5.B.228.166; 5.B.228.169;5.B.228.172; 5.B.228.175; 5.B.228.240; 5.B.228.244; 5.B.229.228;5.B.229.229; 5.B.229.230; 5.B.229.231; 5.B.229.236; 5.B.229.237;5.B.229.238; 5.B.229.239; 5.B.229.154; 5.B.229.157; 5.B.229.166;5.B.229.169; 5.B.229.172; 5.B.229.175; 5.B.229.240; 5.B.229.244;5.B.230.228; 5.B.230.229; 5.B.230.230; 5.B.230.231; 5.B.230.236;5.B.230.237; 5.B.230.238; 5.B.230.239; 5.B.230.154; 5.B.230.157;5.B.230.166; 5.B.230.169; 5.B.230.172; 5.B.230.175; 5.B.230.240;5.B.230.244; 5.B.231.228; 5.B.231.229; 5.B.231.230; 5.B.231.231;5.B.231.236; 5.B.231.237; 5.B.231.238; 5.B.231.239; 5.B.231.154;5.B.231.157; 5.B.231.166; 5.B.231.169; 5.B.231.172; 5.B.231.175;5.B.231.240; 5.B.231.244; 5.B.236.228; 5.B.236.229; 5.B.236.230;5.B.236.231; 5.B.236.236; 5.B.236.237; 5.B.236.238; 5.B.236.239;5.B.236.154; 5.B.236.157; 5.B.236.166; 5.B.236.169; 5.B.236.172;5.B.236.175; 5.B.236.240; 5.B.236.244; 5.B.237.228; 5.B.237.229;5.B.237.230; 5.B.237.231; 5.B.237.236; 5.B.237.237; 5.B.237.238;5.B.237.239; 5.B.237.154; 5.B.237.157; 5.B.237.166; 5.B.237.169;5.B.237.172; 5.B.237.175; 5.B.237.240; 5.B.237.244; 5.B.238.228;5.B.238.229; 5.B.238.230; 5.B.238.231; 5.B.238.236; 5.B.238.237;5.B.238.238; 5.B.238.239; 5.B.238.154; 5.B.238.157; 5.B.238.166;5.B.238.169; 5.B.238.172; 5.B.238.175; 5.B.238.240; 5.B.238.244;5.B.239.228; 5.B.239.229; 5.B.239.230; 5.B.239.231; 5.B.239.236;5.B.239.237; 5.B.239.238; 5.B.239.239; 5.B.239.154; 5.B.239.157;5.B.239.166; 5.B.239.169; 5.B.239.172; 5.B.239.175; 5.B.239.240;5.B.239.244; 5.B.154.228; 5.B.154.229; 5.B.154.230; 5.B.154.231;5.B.154.236; 5.B.154.237; 5.B.154.238; 5.B.154.239; 5.B.154.154;5.B.154.157; 5.B.154.166; 5.B.154.169; 5.B.154.172; 5.B.154.175;5.B.154.240; 5.B.154.244; 5.B.157.228; 5.B.157.229; 5.B.157.230;5.B.157.231; 5.B.157.236; 5.B.157.237; 5.B.157.238; 5.B.157.239;5.B.157.154; 5.B.157.157; 5.B.157.166; 5.B.157.169; 5.B.157.172;5.B.157.175; 5.B.157.240; 5.B.157.244; 5.B.166.228; 5.B.166.229;5.B.166.230; 5.B.166.231; 5.B.166.236; 5.B.166.237; 5.B.166.238;5.B.166.239; 5.B.166.154; 5.B.166.157; 5.B.166.166; 5.B.166.169;5.B.166.172; 5.B.166.175; 5.B.166.240; 5.B.166.244; 5.B.169.228;5.B.169.229; 5.B.169.230; 5.B.169.231; 5.B.169.236; 5.B.169.237;5.B.169.238; 5.B.169.239; 5.B.169.154; 5.B.169.157; 5.B.169.166;5.B.169.169; 5.B.169.172; 5.B.169.175; 5.B.169.240; 5.B.169.244;5.B.172.228; 5.B.172.229; 5.B.172.230; 5.B.172.231; 5.B.172.236;5.B.172.237; 5.B.172.238; 5.B.172.239; 5.B.172.154; 5.B.172.157;5.B.172.166; 5.B.172.169; 5.B.172.172; 5.B.172.175; 5.B.172.240;5.B.172.244; 5.B.175.228; 5.B.175.229; 5.B.175.230; 5.B.175.231;5.B.175.236; 5.B.175.237; 5.B.175.238; 5.B.175.239; 5.B.175.154;5.B.175.157; 5.B.175.166; 5.B.175.169; 5.B.175.172; 5.B.175.175;5.B.175.240; 5.B.175.244; 5.B.240.228; 5.B.240.229; 5.B.240.230;5.B.240.231; 5.B.240.236; 5.B.240.237; 5.B.240.238; 5.B.240.239;5.B.240.154; 5.B.240.157; 5.B.240.166; 5.B.240.169; 5.B.240.172;5.B.240.175; 5.B.240.240; 5.B.240.244; 5.B.244.228; 5.B.244.229;5.B.244.230; 5.B.244.231; 5.B.244.236; 5.B.244.237; 5.B.244.238;5.B.244.239; 5.B.244.154; 5.B.244.157; 5.B.244.166; 5.B.244.169;5.B.244.172; 5.B.244.175; 5.B.244.240; 5.B.244.244; Prodrugs of 5.D5.D.228.228; 5.D.228.229; 5.D.228.230; 5.D.228.231; 5.D.228.236;5.D.228.237; 5.D.228.238; 5.D.228.239; 5.D.228.154; 5.D.228.157;5.D.228.166; 5.D.228.169; 5.D.228.172; 5.D.228.175; 5.D.228.240;5.D.228.244; 5.D.229.228; 5.D.229.229; 5.D.229.230; 5.D.229.231;5.D.229.236; 5.D.229.237; 5.D.229.238; 5.D.229.239; 5.D.229.154;5.D.229.157; 5.D.229.166; 5.D.229.169; 5.D.229.172; 5.D.229.175;5.D.229.240; 5.D.229.244; 5.D.230.228; 5.D.230.229; 5.D.230.230;5.D.230.231; 5.D.230.236; 5.D.230.237; 5.D.230.238; 5.D.230.239;5.D.230.154; 5.D.230.157; 5.D.230.166; 5.D.230.169; 5.D.230.172;5.D.230.175; 5.D.230.240; 5.D.230.244; 5.D.231.228; 5.D.231.229;5.D.231.230; 5.D.231.231; 5.D.231.236; 5.D.231.237; 5.D.231.238;5.D.231.239; 5.D.231.154; 5.D.231.157; 5.D.231.166; 5.D.231.169;5.D.231.172; 5.D.231.175; 5.D.231.240; 5.D.231.244; 5.D.236.228;5.D.236.229; 5.D.236.230; 5.D.236.231; 5.D.236.236; 5.D.236.237;5.D.236.238; 5.D.236.239; 5.D.236.154; 5.D.236.157; 5.D.236.166;5.D.236.169; 5.D.236.172; 5.D.236.175; 5.D.236.240; 5.D.236.244;5.D.237.228; 5.D.237.229; 5.D.237.230; 5.D.237.231; 5.D.237.236;5.D.237.237; 5.D.237.238; 5.D.237.239; 5.D.237.154; 5.D.237.157;5.D.237.166; 5.D.237.169; 5.D.237.172; 5.D.237.175; 5.D.237.240;5.D.237.244; 5.D.238.228; 5.D.238.229; 5.D.238.230; 5.D.238.231;5.D.238.236; 5.D.238.237; 5.D.238.238; 5.D.238.239; 5.D.238.154;5.D.238.157; 5.D.238.166; 5.D.238.169; 5.D.238.172; 5.D.238.175;5.D.238.240; 5.D.238.244; 5.D.239.228; 5.D.239.229; 5.D.239.230;5.D.239.231; 5.D.239.236; 5.D.239.237; 5.D.239.238; 5.D.239.239;5.D.239.154; 5.D.239.157; 5.D.239.166; 5.D.239.169; 5.D.239.172;5.D.239.175; 5.D.239.240; 5.D.239.244; 5.D.154.228; 5.D.154.229;5.D.154.230; 5.D.154.231; 5.D.154.236; 5.D.154.237; 5.D.154.238;5.D.154.239; 5.D.154.154; 5.D.154.157; 5.D.154.166; 5.D.154.169;5.D.154.172; 5.D.154.175; 5.D.154.240; 5.D.154.244; 5.D.157.228;5.D.157.229; 5.D.157.230; 5.D.157.231; 5.D.157.236; 5.D.157.237;5.D.157.238; 5.D.157.239; 5.D.157.154; 5.D.157.157; 5.D.157.166;5.D.157.169; 5.D.157.172; 5.D.157.175; 5.D.157.240; 5.D.157.244;5.D.166.228; 5.D.166.229; 5.D.166.230; 5.D.166.231; 5.D.166.236;5.D.166.237; 5.D.166.238; 5.D.166.239; 5.D.166.154; 5.D.166.157;5.D.166.166; 5.D.166.169; 5.D.166.172; 5.D.166.175; 5.D.166.240;5.D.166.244; 5.D.169.228; 5.D.169.229; 5.D.169.230; 5.D.169.231;5.D.169.236; 5.D.169.237; 5.D.169.238; 5.D.169.239; 5.D.169.154;5.D.169.157; 5.D.169.166; 5.D.169.169; 5.D.169.172; 5.D.169.175;5.D.169.240; 5.D.169.244; 5.D.172.228; 5.D.172.229; 5.D.172.230;5.D.172.231; 5.D.172.236; 5.D.172.237; 5.D.172.238; 5.D.172.239;5.D.172.154; 5.D.172.157; 5.D.172.166; 5.D.172.169; 5.D.172.172;5.D.172.175; 5.D.172.240; 5.D.172.244; 5.D.175.228; 5.D.175.229;5.D.175.230; 5.D.175.231; 5.D.175.236; 5.D.175.237; 5.D.175.238;5.D.175.239; 5.D.175.154; 5.D.175.157; 5.D.175.166; 5.D.175.169;5.D.175.172; 5.D.175.175; 5.D.175.240; 5.D.175.244; 5.D.240.228;5.D.240.229; 5.D.240.230; 5.D.240.231; 5.D.240.236; 5.D.240.237;5.D.240.238; 5.D.240.239; 5.D.240.154; 5.D.240.157; 5.D.240.166;5.D.240.169; 5.D.240.172; 5.D.240.175; 5.D.240.240; 5.D.240.244;5.D.244.228; 5.D.244.229; 5.D.244.230; 5.D.244.231; 5.D.244.236;5.D.244.237; 5.D.244.238; 5.D.244.239; 5.D.244.154; 5.D.244.157;5.D.244.166; 5.D.244.169; 5.D.244.172; 5.D.244.175; 5.D.244.240;5.D.244.244; Prodrugs of 5.E 5.E.228.228; 5.E.228.229; 5.E.228.230;5.E.228.231; 5.E.228.236; 5.E.228.237; 5.E.228.238; 5.E.228.239;5.E.228.154; 5.E.228.157; 5.E.228.166; 5.E.228.169; 5.E.228.172;5.E.228.175; 5.E.228.240; 5.E.228.244; 5.E.229.228; 5.E.229.229;5.E.229.230; 5.E.229.231; 5.E.229.236; 5.E.229.237; 5.E.229.238;5.E.229.239; 5.E.229.154; 5.E.229.157; 5.E.229.166; 5.E.229.169;5.E.229.172; 5.E.229.175; 5.E.229.240; 5.E.229.244; 5.E.230.228;5.E.230.229; 5.E.230.230; 5.E.230.231; 5.E.230.236; 5.E.230.237;5.E.230.238; 5.E.230.239; 5.E.230.154; 5.E.230.157; 5.E.230.166;5.E.230.169; 5.E.230.172; 5.E.230.175; 5.E.230.240; 5.E.230.244;5.E.231.228; 5.E.231.229; 5.E.231.230; 5.E.231.231; 5.E.231.236;5.E.231.237; 5.E.231.238; 5.E.231.239; 5.E.231.154; 5.E.231.157;5.E.231.166; 5.E.231.169; 5.E.231.172; 5.E.231.175; 5.E.231.240;5.E.231.244; 5.E.236.228; 5.E.236.229; 5.E.236.230; 5.E.236.231;5.E.236.236; 5.E.236.237; 5.E.236.238; 5.E.236.239; 5.E.236.154;5.E.236.157; 5.E.236.166; 5.E.236.169; 5.E.236.172; 5.E.236.175;5.E.236.240; 5.E.236.244; 5.E.237.228; 5.E.237.229; 5.E.237.230;5.E.237.231; 5.E.237.236; 5.E.237.237; 5.E.237.238; 5.E.237.239;5.E.237.154; 5.E.237.157; 5.E.237.166; 5.E.237.169; 5.E.237.172;5.E.237.175; 5.E.237.240; 5.E.237.244; 5.E.238.228; 5.E.238.229;5.E.238.230; 5.E.238.231; 5.E.238.236; 5.E.238.237; 5.E.238.238;5.E.238.239; 5.E.238.154; 5.E.238.157; 5.E.238.166; 5.E.238.169;5.E.238.172; 5.E.238.175; 5.E.238.240; 5.E.238.244; 5.E.239.228;5.E.239.229; 5.E.239.230; 5.E.239.231; 5.E.239.236; 5.E.239.237;5.E.239.238; 5.E.239.239; 5.E.239.154; 5.E.239.157; 5.E.239.166;5.E.239.169; 5.E.239.172; 5.E.239.175; 5.E.239.240; 5.E.239.244;5.E.154.228; 5.E.154.229; 5.E.154.230; 5.E.154.231; 5.E.154.236;5.E.154.237; 5.E.154.238; 5.E.154.239; 5.E.154.154; 5.E.154.157;5.E.154.166; 5.E.154.169; 5.E.154.172; 5.E.154.175; 5.E.154.240;5.E.154.244; 5.E.157.228; 5.E.157.229; 5.E.157.230; 5.E.157.231;5.E.157.236; 5.E.157.237; 5.E.157.238; 5.E.157.239; 5.E.157.154;5.E.157.157; 5.E.157.166; 5.E.157.169; 5.E.157.172; 5.E.157.175;5.E.157.240; 5.E.157.244; 5.E.166.228; 5.E.166.229; 5.E.166.230;5.E.166.231; 5.E.166.236; 5.E.166.237; 5.E.166.238; 5.E.166.239;5.E.166.154; 5.E.166.157; 5.E.166.166; 5.E.166.169; 5.E.166.172;5.E.166.175; 5.E.166.240; 5.E.166.244; 5.E.169.228; 5.E.169.229;5.E.169.230; 5.E.169.231; 5.E.169.236; 5.E.169.237; 5.E.169.238;5.E.169.239; 5.E.169.154; 5.E.169.157; 5.E.169.166; 5.E.169.169;5.E.169.172; 5.E.169.175; 5.E.169.240; 5.E.169.244; 5.E.172.228;5.E.172.229; 5.E.172.230; 5.E.172.231; 5.E.172.236; 5.E.172.237;5.E.172.238; 5.E.172.239; 5.E.172.154; 5.E.172.157; 5.E.172.166;5.E.172.169; 5.E.172.172; 5.E.172.175; 5.E.172.240; 5.E.172.244;5.E.175.228; 5.E.175.229; 5.E.175.230; 5.E.175.231; 5.E.175.236;5.E.175.237; 5.E.175.238; 5.E.175.239; 5.E.175.154; 5.E.175.157;5.E.175.166; 5.E.175.169; 5.E.175.172; 5.E.175.175; 5.E.175.240;5.E.175.244; 5.E.240.228; 5.E.240.229; 5.E.240.230; 5.E.240.231;5.E.240.236; 5.E.240.237; 5.E.240.238; 5.E.240.239; 5.E.240.154;5.E.240.157; 5.E.240.166; 5.E.240.169; 5.E.240.172; 5.E.240.175;5.E.240.240; 5.E.240.244; 5.E.244.228; 5.E.244.229; 5.E.244.230;5.E.244.231; 5.E.244.236; 5.E.244.237; 5.E.244.238; 5.E.244.239;5.E.244.154; 5.E.244.157; 5.E.244.166; 5.E.244.169; 5.E.244.172;5.E.244.175; 5.E.244.240; 5.E.244.244; Prodrugs of 5.G 5.G.228.228;5.G.228.229; 5.G.228.230; 5.G.228.231; 5.G.228.236; 5.G.228.237;5.G.228.238; 5.G.228.239; 5.G.228.154; 5.G.228.157; 5.G.228.166;5.G.228.169; 5.G.228.172; 5.G.228.175; 5.G.228.240; 5.G.228.244;5.G.229.228; 5.G.229.229; 5.G.229.230; 5.G.229.231; 5.G.229.236;5.G.229.237; 5.G.229.238; 5.G.229.239; 5.G.229.154; 5.G.229.157;5.G.229.166; 5.G.229.169; 5.G.229.172; 5.G.229.175; 5.G.229.240;5.G.229.244; 5.G.230.228; 5.G.230.229; 5.G.230.230; 5.G.230.231;5.G.230.236; 5.G.230.237; 5.G.230.238; 5.G.230.239; 5.G.230.154;5.G.230.157; 5.G.230.166; 5.G.230.169; 5.G.230.172; 5.G.230.175;5.G.230.240; 5.G.230.244; 5.G.231.228; 5.G.231.229; 5.G.231.230;5.G.231.231; 5.G.231.236; 5.G.231.237; 5.G.231.238; 5.G.231.239;5.G.231.154; 5.G.231.157; 5.G.231.166; 5.G.231.169; 5.G.231.172;5.G.231.175; 5.G.231.240; 5.G.231.244; 5.G.236.228; 5.G.236.229;5.G.236.230; 5.G.236.231; 5.G.236.236; 5.G.236.237; 5.G.236.238;5.G.236.239; 5.G.236.154; 5.G.236.157; 5.G.236.166; 5.G.236.169;5.G.236.172; 5.G.236.175; 5.G.236.240; 5.G.236.244; 5.G.237.228;5.G.237.229; 5.G.237.230; 5.G.237.231; 5.G.237.236; 5.G.237.237;5.G.237.238; 5.G.237.239; 5.G.237.154; 5.G.237.157; 5.G.237.166;5.G.237.169; 5.G.237.172; 5.G.237.175; 5.G.237.240; 5.G.237.244;5.G.238.228; 5.G.238.229; 5.G.238.230; 5.G.238.231; 5.G.238.236;5.G.238.237; 5.G.238.238; 5.G.238.239; 5.G.238.154; 5.G.238.157;5.G.238.166; 5.G.238.169; 5.G.238.172; 5.G.238.175; 5.G.238.240;5.G.238.244; 5.G.239.228; 5.G.239.229; 5.G.239.230; 5.G.239.231;5.G.239.236; 5.G.239.237; 5.G.239.238; 5.G.239.239; 5.G.239.154;5.G.239.157; 5.G.239.166; 5.G.239.169; 5.G.239.172; 5.G.239.175;5.G.239.240; 5.G.239.244; 5.G.154.228; 5.G.154.229; 5.G.154.230;5.G.154.231; 5.G.154.236; 5.G.154.237; 5.G.154.238; 5.G.154.239;5.G.154.154; 5.G.154.157; 5.G.154.166; 5.G.154.169; 5.G.154.172;5.G.154.175; 5.G.154.240; 5.G.154.244; 5.G.157.228; 5.G.157.229;5.G.157.230; 5.G.157.231; 5.G.157.236; 5.G.157.237; 5.G.157.238;5.G.157.239; 5.G.157.154; 5.G.157.157; 5.G.157.166; 5.G.157.169;5.G.157.172; 5.G.157.175; 5.G.157.240; 5.G.157.244; 5.G.166.228;5.G.166.229; 5.G.166.230; 5.G.166.231; 5.G.166.236; 5.G.166.237;5.G.166.238; 5.G.166.239; 5.G.166.154; 5.G.166.157; 5.G.166.166;5.G.166.169; 5.G.166.172; 5.G.166.175; 5.G.166.240; 5.G.166.244;5.G.169.228; 5.G.169.229; 5.G.169.230; 5.G.169.231; 5.G.169.236;5.G.169.237; 5.G.169.238; 5.G.169.239; 5.G.169.154; 5.G.169.157;5.G.169.166; 5.G.169.169; 5.G.169.172; 5.G.169.175; 5.G.169.240;5.G.169.244; 5.G.172.228; 5.G.172.229; 5.G.172.230; 5.G.172.231;5.G.172.236; 5.G.172.237; 5.G.172.238; 5.G.172.239; 5.G.172.154;5.G.172.157; 5.G.172.166; 5.G.172.169; 5.G.172.172; 5.G.172.175;5.G.172.240; 5.G.172.244; 5.G.175.228; 5.G.175.229; 5.G.175.230;5.G.175.231; 5.G.175.236; 5.G.175.237; 5.G.175.238; 5.G.175.239;5.G.175.154; 5.G.175.157; 5.G.175.166; 5.G.175.169; 5.G.175.172;5.G.175.175; 5.G.175.240; 5.G.175.244; 5.G.240.228; 5.G.240.229;5.G.240.230; 5.G.240.231; 5.G.240.236; 5.G.240.237; 5.G.240.238;5.G.240.239; 5.G.240.154; 5.G.240.157; 5.G.240.166; 5.G.240.169;5.G.240.172; 5.G.240.175; 5.G.240.240; 5.G.240.244; 5.G.244.228;5.G.244.229; 5.G.244.230; 5.G.244.231; 5.G.244.236; 5.G.244.237;5.G.244.238; 5.G.244.239; 5.G.244.154; 5.G.244.157; 5.G.244.166;5.G.244.169; 5.G.244.172; 5.G.244.175; 5.G.244.240; 5.G.244.244;Prodrugs of 5.I 5.I.228.228; 5.I.228.229; 5.I.228.230; 5.I.228.231;5.I.228.236; 5.I.228.237; 5.I.228.238; 5.I.228.239; 5.I.228.154;5.I.228.157; 5.I.228.166; 5.I.228.169; 5.I.228.172; 5.I.228.175;5.I.228.240; 5.I.228.244; 5.I.229.228; 5.I.229.229; 5.I.229.230;5.I.229.231; 5.I.229.236; 5.I.229.237; 5.I.229.238; 5.I.229.239;5.I.229.154; 5.I.229.157; 5.I.229.166; 5.I.229.169; 5.I.229.172;5.I.229.175; 5.I.229.240; 5.I.229.244; 5.I.230.228; 5.I.230.229;5.I.230.230; 5.I.230.231; 5.I.230.236; 5.I.230.237; 5.I.230.238;5.I.230.239; 5.I.230.154; 5.I.230.157; 5.I.230.166; 5.I.230.169;5.I.230.172; 5.I.230.175; 5.I.230.240; 5.I.230.244; 5.I.231.228;5.I.231.229; 5.I.231.230; 5.I.231.231; 5.I.231.236; 5.I.231.237;5.I.231.238; 5.I.231.239; 5.I.231.154; 5.I.231.157; 5.I.231.166;5.I.231.169; 5.I.231.172; 5.I.231.175; 5.I.231.240; 5.I.231.244;5.I.236.228; 5.I.236.229; 5.I.236.230; 5.I.236.231; 5.I.236.236;5.I.236.237; 5.I.236.238; 5.I.236.239; 5.I.236.154; 5.I.236.157;5.I.236.166; 5.I.236.169; 5.I.236.172; 5.I.236.175; 5.I.236.240;5.I.236.244; 5.I.237.228; 5.I.237.229; 5.I.237.230; 5.I.237.231;5.I.237.236; 5.I.237.237; 5.I.237.238; 5.I.237.239; 5.I.237.154;5.I.237.157; 5.I.237.166; 5.I.237.169; 5.I.237.172; 5.I.237.175;5.I.237.240; 5.I.237.244; 5.I.238.228; 5.I.238.229; 5.I.238.230;5.I.238.231; 5.I.238.236; 5.I.238.237; 5.I.238.238; 5.I.238.239;5.I.238.154; 5.I.238.157; 5.I.238.166; 5.I.238.169; 5.I.238.172;5.I.238.175; 5.I.238.240; 5.I.238.244; 5.I.239.228; 5.I.239.229;5.I.239.230; 5.I.239.231; 5.I.239.236; 5.I.239.237; 5.I.239.238;5.I.239.239; 5.I.239.154; 5.I.239.157; 5.I.239.166; 5.I.239.169;5.I.239.172; 5.I.239.175; 5.I.239.240; 5.I.239.244; 5.I.154.228;5.I.154.229; 5.I.154.230; 5.I.154.231; 5.I.154.236; 5.I.154.237;5.I.154.238; 5.I.154.239; 5.I.154.154; 5.I.154.157; 5.I.154.166;5.I.154.169; 5.I.154.172; 5.I.154.175; 5.I.154.240; 5.I.154.244;5.I.157.228; 5.I.157.229; 5.I.157.230; 5.I.157.231; 5.I.157.236;5.I.157.237; 5.I.157.238; 5.I.157.239; 5.I.157.154; 5.I.157.157;5.I.157.166; 5.I.157.169; 5.I.157.172; 5.I.157.175; 5.I.157.240;5.I.157.244; 5.I.166.228; 5.I.166.229; 5.I.166.230; 5.I.166.231;5.I.166.236; 5.I.166.237; 5.I.166.238; 5.I.166.239; 5.I.166.154;5.I.166.157; 5.I.166.166; 5.I.166.169; 5.I.166.172; 5.I.166.175;5.I.166.240; 5.I.166.244; 5.I.169.228; 5.I.169.229; 5.I.169.230;5.I.169.231; 5.I.169.236; 5.I.169.237; 5.I.169.238; 5.I.169.239;5.I.169.154; 5.I.169.157; 5.I.169.166; 5.I.169.169; 5.I.169.172;5.I.169.175; 5.I.169.240; 5.I.169.244; 5.I.172.228; 5.I.172.229;5.I.172.230; 5.I.172.231; 5.I.172.236; 5.I.172.237; 5.I.172.238;5.I.172.239; 5.I.172.154; 5.I.172.157; 5.I.172.166; 5.I.172.169;5.I.172.172; 5.I.172.175; 5.I.172.240; 5.I.172.244; 5.I.175.228;5.I.175.229; 5.I.175.230; 5.I.175.231; 5.I.175.236; 5.I.175.237;5.I.175.238; 5.I.175.239; 5.I.175.154; 5.I.175.157; 5.I.175.166;5.I.175.169; 5.I.175.172; 5.I.175.175; 5.I.175.240; 5.I.175.244;5.I.240.228; 5.I.240.229; 5.I.240.230; 5.I.240.231; 5.I.240.236;5.I.240.237; 5.I.240.238; 5.I.240.239; 5.I.240.154; 5.I.240.157;5.I.240.166; 5.I.240.169; 5.I.240.172; 5.I.240.175; 5.I.240.240;5.I.240.244; 5.I.244.228; 5.I.244.229; 5.I.244.230; 5.I.244.231;5.I.244.236; 5.I.244.237; 5.I.244.238; 5.I.244.239; 5.I.244.154;5.I.244.157; 5.I.244.166; 5.I.244.169; 5.I.244.172; 5.I.244.175;5.I.244.240; 5.I.244.244; Prodrugs of 5.J 5.J.228.228; 5.J.228.229;5.J.228.230; 5.J.228.231; 5.J.228.236; 5.J.228.237; 5.J.228.238;5.J.228.239; 5.J.228.154; 5.J.228.157; 5.J.228.166; 5.J.228.169;5.J.228.172; 5.J.228.175; 5.J.228.240; 5.J.228.244; 5.J.229.228;5.J.229.229; 5.J.229.230; 5.J.229.231; 5.J.229.236; 5.J.229.237;5.J.229.238; 5.J.229.239; 5.J.229.154; 5.J.229.157; 5.J.229.166;5.J.229.169; 5.J.229.172; 5.J.229.175; 5.J.229.240; 5.J.229.244;5.J.230.228; 5.J.230.229; 5.J.230.230; 5.J.230.231; 5.J.230.236;5.J.230.237; 5.J.230.238; 5.J.230.239; 5.J.230.154; 5.J.230.157;5.J.230.166; 5.J.230.169; 5.J.230.172; 5.J.230.175; 5.J.230.240;5.J.230.244; 5.J.231.228; 5.J.231.229; 5.J.231.230; 5.J.231.231;5.J.231.236; 5.J.231.237; 5.J.231.238; 5.J.231.239; 5.J.231.154;5.J.231.157; 5.J.231.166; 5.J.231.169; 5.J.231.172; 5.J.231.175;5.J.231.240; 5.J.231.244; 5.J.236.228; 5.J.236.229; 5.J.236.230;5.J.236.231; 5.J.236.236; 5.J.236.237; 5.J.236.238; 5.J.236.239;5.J.236.154; 5.J.236.157; 5.J.236.166; 5.J.236.169; 5.J.236.172;5.J.236.175; 5.J.236.240; 5.J.236.244; 5.J.237.228; 5.J.237.229;5.J.237.230; 5.J.237.231; 5.J.237.236; 5.J.237.237; 5.J.237.238;5.J.237.239; 5.J.237.154; 5.J.237.157; 5.J.237.166; 5.J.237.169;5.J.237.172; 5.J.237.175; 5.J.237.240; 5.J.237.244; 5.J.238.228;5.J.238.229; 5.J.238.230; 5.J.238.231; 5.J.238.236; 5.J.238.237;5.J.238.238; 5.J.238.239; 5.J.238.154; 5.J.238.157; 5.J.238.166;5.J.238.169; 5.J.238.172; 5.J.238.175; 5.J.238.240; 5.J.238.244;5.J.239.228; 5.J.239.229; 5.J.239.230; 5.J.239.231; 5.J.239.236;5.J.239.237; 5.J.239.238; 5.J.239.239; 5.J.239.154; 5.J.239.157;5.J.239.166; 5.J.239.169; 5.J.239.172; 5.J.239.175; 5.J.239.240;5.J.239.244; 5.J.154.228; 5.J.154.229; 5.J.154.230; 5.J.154.231;5.J.154.236; 5.J.154.237; 5.J.154.238; 5.J.154.239; 5.J.154.154;5.J.154.157; 5.J.154.166; 5.J.154.169; 5.J.154.172; 5.J.154.175;5.J.154.240; 5.J.154.244; 5.J.157.228; 5.J.157.229; 5.J.157.230;5.J.157.231; 5.J.157.236; 5.J.157.237; 5.J.157.238; 5.J.157.239;5.J.157.154; 5.J.157.157; 5.J.157.166; 5.J.157.169; 5.J.157.172;5.J.157.175; 5.J.157.240; 5.J.157.244; 5.J.166.228; 5.J.166.229;5.J.166.230; 5.J.166.231; 5.J.166.236; 5.J.166.237; 5.J.166.238;5.J.166.239; 5.J.166.154; 5.J.166.157; 5.J.166.166; 5.J.166.169;5.J.166.172; 5.J.166.175; 5.J.166.240; 5.J.166.244; 5.J.169.228;5.J.169.229; 5.J.169.230; 5.J.169.231; 5.J.169.236; 5.J.169.237;5.J.169.238; 5.J.169.239; 5.J.169.154; 5.J.169.157; 5.J.169.166;5.J.169.169; 5.J.169.172; 5.J.169.175; 5.J.169.240; 5.J.169.244;5.J.172.228; 5.J.172.229; 5.J.172.230; 5.J.172.231; 5.J.172.236;5.J.172.237; 5.J.172.238; 5.J.172.239; 5.J.172.154; 5.J.172.157;5.J.172.166; 5.J.172.169; 5.J.172.172; 5.J.172.175; 5.J.172.240;5.J.172.244; 5.J.175.228; 5.J.175.229; 5.J.175.230; 5.J.175.231;5.J.175.236; 5.J.175.237; 5.J.175.238; 5.J.175.239; 5.J.175.154;5.J.175.157; 5.J.175.166; 5.J.175.169; 5.J.175.172; 5.J.175.175;5.J.175.240; 5.J.175.244; 5.J.240.228; 5.J.240.229; 5.J.240.230;5.J.240.231; 5.J.240.236; 5.J.240.237; 5.J.240.238; 5.J.240.239;5.J.240.154; 5.J.240.157; 5.J.240.166; 5.J.240.169; 5.J.240.172;5.J.240.175; 5.J.240.240; 5.J.240.244; 5.J.244.228; 5.J.244.229;5.J.244.230; 5.J.244.231; 5.J.244.236; 5.J.244.237; 5.J.244.238;5.J.244.239; 5.J.244.154; 5.J.244.157; 5.J.244.166; 5.J.244.169;5.J.244.172; 5.J.244.175; 5.J.244.240; 5.J.244.244; Prodrugs of 5.L5.L.228.228; 5.L.228.229; 5.L.228.230; 5.L.228.231; 5.L.228.236;5.L.228.237; 5.L.228.238; 5.L.228.239; 5.L.228.154; 5.L.228.157;5.L.228.166; 5.L.228.169; 5.L.228.172; 5.L.228.175; 5.L.228.240;5.L.228.244; 5.L.229.228; 5.L.229.229; 5.L.229.230; 5.L.229.231;5.L.229.236; 5.L.229.237; 5.L.229.238; 5.L.229.239; 5.L.229.154;5.L.229.157; 5.L.229.166; 5.L.229.169; 5.L.229.172; 5.L.229.175;5.L.229.240; 5.L.229.244; 5.L.230.228; 5.L.230.229; 5.L.230.230;5.L.230.231; 5.L.230.236; 5.L.230.237; 5.L.230.238; 5.L.230.239;5.L.230.154; 5.L.230.157; 5.L.230.166; 5.L.230.169; 5.L.230.172;5.L.230.175; 5.L.230.240; 5.L.230.244; 5.L.231.228; 5.L.231.229;5.L.231.230; 5.L.231.231; 5.L.231.236; 5.L.231.237; 5.L.231.238;5.L.231.239; 5.L.231.154; 5.L.231.157; 5.L.231.166; 5.L.231.169;5.L.231.172; 5.L.231.175; 5.L.231.240; 5.L.231.244; 5.L.236.228;5.L.236.229; 5.L.236.230; 5.L.236.231; 5.L.236.236; 5.L.236.237;5.L.236.238; 5.L.236.239; 5.L.236.154; 5.L.236.157; 5.L.236.166;5.L.236.169; 5.L.236.172; 5.L.236.175; 5.L.236.240; 5.L.236.244;5.L.237.228; 5.L.237.229; 5.L.237.230; 5.L.237.231; 5.L.237.236;5.L.237.237; 5.L.237.238; 5.L.237.239; 5.L.237.154; 5.L.237.157;5.L.237.166; 5.L.237.169; 5.L.237.172; 5.L.237.175; 5.L.237.240;5.L.237.244; 5.L.238.228; 5.L.238.229; 5.L.238.230; 5.L.238.231;5.L.238.236; 5.L.238.237; 5.L.238.238; 5.L.238.239; 5.L.238.154;5.L.238.157; 5.L.238.166; 5.L.238.169; 5.L.238.172; 5.L.238.175;5.L.238.240; 5.L.238.244; 5.L.239.228; 5.L.239.229; 5.L.239.230;5.L.239.231; 5.L.239.236; 5.L.239.237; 5.L.239.238; 5.L.239.239;5.L.239.154; 5.L.239.157; 5.L.239.166; 5.L.239.169; 5.L.239.172;5.L.239.175; 5.L.239.240; 5.L.239.244; 5.L.154.228; 5.L.154.229;5.L.154.230; 5.L.154.231; 5.L.154.236; 5.L.154.237; 5.L.154.238;5.L.154.239; 5.L.154.154; 5.L.154.157; 5.L.154.166; 5.L.154.169;5.L.154.172; 5.L.154.175; 5.L.154.240; 5.L.154.244; 5.L.157.228;5.L.157.229; 5.L.157.230; 5.L.157.231; 5.L.157.236; 5.L.157.237;5.L.157.238; 5.L.157.239; 5.L.157.154; 5.L.157.157; 5.L.157.166;5.L.157.169; 5.L.157.172; 5.L.157.175; 5.L.157.240; 5.L.157.244;5.L.166.228; 5.L.166.229; 5.L.166.230; 5.L.166.231; 5.L.166.236;5.L.166.237; 5.L.166.238; 5.L.166.239; 5.L.166.154; 5.L.166.157;5.L.166.166; 5.L.166.169; 5.L.166.172; 5.L.166.175; 5.L.166.240;5.L.166.244; 5.L.169.228; 5.L.169.229; 5.L.169.230; 5.L.169.231;5.L.169.236; 5.L.169.237; 5.L.169.238; 5.L.169.239; 5.L.169.154;5.L.169.157; 5.L.169.166; 5.L.169.169; 5.L.169.172; 5.L.169.175;5.L.169.240; 5.L.169.244; 5.L.172.228; 5.L.172.229; 5.L.172.230;5.L.172.231; 5.L.172.236; 5.L.172.237; 5.L.172.238; 5.L.172.239;5.L.172.154; 5.L.172.157; 5.L.172.166; 5.L.172.169; 5.L.172.172;5.L.172.175; 5.L.172.240; 5.L.172.244; 5.L.175.228; 5.L.175.229;5.L.175.230; 5.L.175.231; 5.L.175.236; 5.L.175.237; 5.L.175.238;5.L.175.239; 5.L.175.154; 5.L.175.157; 5.L.175.166; 5.L.175.169;5.L.175.172; 5.L.175.175; 5.L.175.240; 5.L.175.244; 5.L.240.228;5.L.240.229; 5.L.240.230; 5.L.240.231; 5.L.240.236; 5.L.240.237;5.L.240.238; 5.L.240.239; 5.L.240.154; 5.L.240.157; 5.L.240.166;5.L.240.169; 5.L.240.172; 5.L.240.175; 5.L.240.240; 5.L.240.244;5.L.244.228; 5.L.244.229; 5.L.244.230; 5.L.244.231; 5.L.244.236;5.L.244.237; 5.L.244.238; 5.L.244.239; 5.L.244.154; 5.L.244.157;5.L.244.166; 5.L.244.169; 5.L.244.172; 5.L.244.175; 5.L.244.240;5.L.244.244; Prodrugs of 5.O 5.O.228.228; 5.O.228.229; 5.O.228.230;5.O.228.231; 5.O.228.236; 5.O.228.237; 5.O.228.238; 5.O.228.239;5.O.228.154; 5.O.228.157; 5.O.228.166; 5.O.228.169; 5.O.228.172;5.O.228.175; 5.O.228.240; 5.O.228.244; 5.O.229.228; 5.O.229.229;5.O.229.230; 5.O.229.231; 5.O.229.236; 5.O.229.237; 5.O.229.238;5.O.229.239; 5.O.229.154; 5.O.229.157; 5.O.229.166; 5.O.229.169;5.O.229.172; 5.O.229.175; 5.O.229.240; 5.O.229.244; 5.O.230.228;5.O.230.229; 5.O.230.230; 5.O.230.231; 5.O.230.236; 5.O.230.237;5.O.230.238; 5.O.230.239; 5.O.230.154; 5.O.230.157; 5.O.230.166;5.O.230.169; 5.O.230.172; 5.O.230.175; 5.O.230.240; 5.O.230.244;5.O.231.228; 5.O.231.229; 5.O.231.230; 5.O.231.231; 5.O.231.236;5.O.231.237; 5.O.231.238; 5.O.231.239; 5.O.231.154; 5.O.231.157;5.O.231.166; 5.O.231.169; 5.O.231.172; 5.O.231.175; 5.O.231.240;5.O.231.244; 5.O.236.228; 5.O.236.229; 5.O.236.230; 5.O.236.231;5.O.236.236; 5.O.236.237; 5.O.236.238; 5.O.236.239; 5.O.236.154;5.O.236.157; 5.O.236.166; 5.O.236.169; 5.O.236.172; 5.O.236.175;5.O.236.240; 5.O.236.244; 5.O.237.228; 5.O.237.229; 5.O.237.230;5.O.237.231; 5.O.237.236; 5.O.237.237; 5.O.237.238; 5.O.237.239;5.O.237.154; 5.O.237.157; 5.O.237.166; 5.O.237.169; 5.O.237.172;5.O.237.175; 5.O.237.240; 5.O.237.244; 5.O.238.228; 5.O.238.229;5.O.238.230; 5.O.238.231; 5.O.238.236; 5.O.238.237; 5.O.238.238;5.O.238.239; 5.O.238.154; 5.O.238.157; 5.O.238.166; 5.O.238.169;5.O.238.172; 5.O.238.175; 5.O.238.240; 5.O.238.244; 5.O.239.228;5.O.239.229; 5.O.239.230; 5.O.239.231; 5.O.239.236; 5.O.239.237;5.O.239.238; 5.O.239.239; 5.O.239.154; 5.O.239.157; 5.O.239.166;5.O.239.169; 5.O.239.172; 5.O.239.175; 5.O.239.240; 5.O.239.244;5.O.154.228; 5.O.154.229; 5.O.154.230; 5.O.154.231; 5.O.154.236;5.O.154.237; 5.O.154.238; 5.O.154.239; 5.O.154.154; 5.O.154.157;5.O.154.166; 5.O.154.169; 5.O.154.172; 5.O.154.175; 5.O.154.240;5.O.154.244; 5.O.157.228; 5.O.157.229; 5.O.157.230; 5.O.157.231;5.O.157.236; 5.O.157.237; 5.O.157.238; 5.O.157.239; 5.O.157.154;5.O.157.157; 5.O.157.166; 5.O.157.169; 5.O.157.172; 5.O.157.175;5.O.157.240; 5.O.157.244; 5.O.166.228; 5.O.166.229; 5.O.166.230;5.O.166.231; 5.O.166.236; 5.O.166.237; 5.O.166.238; 5.O.166.239;5.O.166.154; 5.O.166.157; 5.O.166.166; 5.O.166.169; 5.O.166.172;5.O.166.175; 5.O.166.240; 5.O.166.244; 5.O.169.228; 5.O.169.229;5.O.169.230; 5.O.169.231; 5.O.169.236; 5.O.169.237; 5.O.169.238;5.O.169.239; 5.O.169.154; 5.O.169.157; 5.O.169.166; 5.O.169.169;5.O.169.172; 5.O.169.175; 5.O.169.240; 5.O.169.244; 5.O.172.228;5.O.172.229; 5.O.172.230; 5.O.172.231; 5.O.172.236; 5.O.172.237;5.O.172.238; 5.O.172.239; 5.O.172.154; 5.O.172.157; 5.O.172.166;5.O.172.169; 5.O.172.172; 5.O.172.175; 5.O.172.240; 5.O.172.244;5.O.175.228; 5.O.175.229; 5.O.175.230; 5.O.175.231; 5.O.175.236;5.O.175.237; 5.O.175.238; 5.O.175.239; 5.O.175.154; 5.O.175.157;5.O.175.166; 5.O.175.169; 5.O.175.172; 5.O.175.175; 5.O.175.240;5.O.175.244; 5.O.240.228; 5.O.240.229; 5.O.240.230; 5.O.240.231;5.O.240.236; 5.O.240.237; 5.O.240.238; 5.O.240.239; 5.O.240.154;5.O.240.157; 5.O.240.166; 5.O.240.169; 5.O.240.172; 5.O.240.175;5.O.240.240; 5.O.240.244; 5.O.244.228; 5.O.244.229; 5.O.244.230;5.O.244.231; 5.O.244.236; 5.O.244.237; 5.O.244.238; 5.O.244.239;5.O.244.154; 5.O.244.157; 5.O.244.166; 5.O.244.169; 5.O.244.172;5.O.244.175; 5.O.244.240; 5.O.244.244; Prodrugs of 5.P 5.P.228.228;5.P.228.229; 5.P.228.230; 5.P.228.231; 5.P.228.236; 5.P.228.237;5.P.228.238; 5.P.228.239; 5.P.228.154; 5.P.228.157; 5.P.228.166;5.P.228.169; 5.P.228.172; 5.P.228.175; 5.P.228.240; 5.P.228.244;5.P.229.228; 5.P.229.229; 5.P.229.230; 5.P.229.231; 5.P.229.236;5.P.229.237; 5.P.229.238; 5.P.229.239; 5.P.229.154; 5.P.229.157;5.P.229.166; 5.P.229.169; 5.P.229.172; 5.P.229.175; 5.P.229.240;5.P.229.244; 5.P.230.228; 5.P.230.229; 5.P.230.230; 5.P.230.231;5.P.230.236; 5.P.230.237; 5.P.230.238; 5.P.230.239; 5.P.230.154;5.P.230.157; 5.P.230.166; 5.P.230.169; 5.P.230.172; 5.P.230.175;5.P.230.240; 5.P.230.244; 5.P.231.228; 5.P.231.229; 5.P.231.230;5.P.231.231; 5.P.231.236; 5.P.231.237; 5.P.231.238; 5.P.231.239;5.P.231.154; 5.P.231.157; 5.P.231.166; 5.P.231.169; 5.P.231.172;5.P.231.175; 5.P.231.240; 5.P.231.244; 5.P.236.228; 5.P.236.229;5.P.236.230; 5.P.236.231; 5.P.236.236; 5.P.236.237; 5.P.236.238;5.P.236.239; 5.P.236.154; 5.P.236.157; 5.P.236.166; 5.P.236.169;5.P.236.172; 5.P.236.175; 5.P.236.240; 5.P.236.244; 5.P.237.228;5.P.237.229; 5.P.237.230; 5.P.237.231; 5.P.237.236; 5.P.237.237;5.P.237.238; 5.P.237.239; 5.P.237.154; 5.P.237.157; 5.P.237.166;5.P.237.169; 5.P.237.172; 5.P.237.175; 5.P.237.240; 5.P.237.244;5.P.238.228; 5.P.238.229; 5.P.238.230; 5.P.238.231; 5.P.238.236;5.P.238.237; 5.P.238.238; 5.P.238.239; 5.P.238.154; 5.P.238.157;5.P.238.166; 5.P.238.169; 5.P.238.172; 5.P.238.175; 5.P.238.240;5.P.238.244; 5.P.239.228; 5.P.239.229; 5.P.239.230; 5.P.239.231;5.P.239.236; 5.P.239.237; 5.P.239.238; 5.P.239.239; 5.P.239.154;5.P.239.157; 5.P.239.166; 5.P.239.169; 5.P.239.172; 5.P.239.175;5.P.239.240; 5.P.239.244; 5.P.154.228; 5.P.154.229; 5.P.154.230;5.P.154.231; 5.P.154.236; 5.P.154.237; 5.P.154.238; 5.P.154.239;5.P.154.154; 5.P.154.157; 5.P.154.166; 5.P.154.169; 5.P.154.172;5.P.154.175; 5.P.154.240; 5.P.154.244; 5.P.157.228; 5.P.157.229;5.P.157.230; 5.P.157.231; 5.P.157.236; 5.P.157.237; 5.P.157.238;5.P.157.239; 5.P.157.154; 5.P.157.157; 5.P.157.166; 5.P.157.169;5.P.157.172; 5.P.157.175; 5.P.157.240; 5.P.157.244; 5.P.166.228;5.P.166.229; 5.P.166.230; 5.P.166.231; 5.P.166.236; 5.P.166.237;5.P.166.238; 5.P.166.239; 5.P.166.154; 5.P.166.157; 5.P.166.166;5.P.166.169; 5.P.166.172; 5.P.166.175; 5.P.166.240; 5.P.166.244;5.P.169.228; 5.P.169.229; 5.P.169.230; 5.P.169.231; 5.P.169.236;5.P.169.237; 5.P.169.238; 5.P.169.239; 5.P.169.154; 5.P.169.157;5.P.169.166; 5.P.169.169; 5.P.169.172; 5.P.169.175; 5.P.169.240;5.P.169.244; 5.P.172.228; 5.P.172.229; 5.P.172.230; 5.P.172.231;5.P.172.236; 5.P.172.237; 5.P.172.238; 5.P.172.239; 5.P.172.154;5.P.172.157; 5.P.172.166; 5.P.172.169; 5.P.172.172; 5.P.172.175;5.P.172.240; 5.P.172.244; 5.P.175.228; 5.P.175.229; 5.P.175.230;5.P.175.231; 5.P.175.236; 5.P.175.237; 5.P.175.238; 5.P.175.239;5.P.175.154; 5.P.175.157; 5.P.175.166; 5.P.175.169; 5.P.175.172;5.P.175.175; 5.P.175.240; 5.P.175.244; 5.P.240.228; 5.P.240.229;5.P.240.230; 5.P.240.231; 5.P.240.236; 5.P.240.237; 5.P.240.238;5.P.240.239; 5.P.240.154; 5.P.240.157; 5.P.240.166; 5.P.240.169;5.P.240.172; 5.P.240.175; 5.P.240.240; 5.P.240.244; 5.P.244.228;5.P.244.229; 5.P.244.230; 5.P.244.231; 5.P.244.236; 5.P.244.237;5.P.244.238; 5.P.244.239; 5.P.244.154; 5.P.244.157; 5.P.244.166;5.P.244.169; 5.P.244.172; 5.P.244.175; 5.P.244.240; 5.P.244.244;Prodrugs of 5.U 5.U.228.228; 5.U.228.229; 5.U.228.230; 5.U.228.231;5.U.228.236; 5.U.228.237; 5.U.228.238; 5.U.228.239; 5.U.228.154;5.U.228.157; 5.U.228.166; 5.U.228.169; 5.U.228.172; 5.U.228.175;5.U.228.240; 5.U.228.244; 5.U.229.228; 5.U.229.229; 5.U.229.230;5.U.229.231; 5.U.229.236; 5.U.229.237; 5.U.229.238; 5.U.229.239;5.U.229.154; 5.U.229.157; 5.U.229.166; 5.U.229.169; 5.U.229.172;5.U.229.175; 5.U.229.240; 5.U.229.244; 5.U.230.228; 5.U.230.229;5.U.230.230; 5.U.230.231; 5.U.230.236; 5.U.230.237; 5.U.230.238;5.U.230.239; 5.U.230.154; 5.U.230.157; 5.U.230.166; 5.U.230.169;5.U.230.172; 5.U.230.175; 5.U.230.240; 5.U.230.244; 5.U.231.228;5.U.231.229; 5.U.231.230; 5.U.231.231; 5.U.231.236; 5.U.231.237;5.U.231.238; 5.U.231.239; 5.U.231.154; 5.U.231.157; 5.U.231.166;5.U.231.169; 5.U.231.172; 5.U.231.175; 5.U.231.240; 5.U.231.244;5.U.236.228; 5.U.236.229; 5.U.236.230; 5.U.236.231; 5.U.236.236;5.U.236.237; 5.U.236.238; 5.U.236.239; 5.U.236.154; 5.U.236.157;5.U.236.166; 5.U.236.169; 5.U.236.172; 5.U.236.175; 5.U.236.240;5.U.236.244; 5.U.237.228; 5.U.237.229; 5.U.237.230; 5.U.237.231;5.U.237.236; 5.U.237.237; 5.U.237.238; 5.U.237.239; 5.U.237.154;5.U.237.157; 5.U.237.166; 5.U.237.169; 5.U.237.172; 5.U.237.175;5.U.237.240; 5.U.237.244; 5.U.238.228; 5.U.238.229; 5.U.238.230;5.U.238.231; 5.U.238.236; 5.U.238.237; 5.U.238.238; 5.U.238.239;5.U.238.154; 5.U.238.157; 5.U.238.166; 5.U.238.169; 5.U.238.172;5.U.238.175; 5.U.238.240; 5.U.238.244; 5.U.239.228; 5.U.239.229;5.U.239.230; 5.U.239.231; 5.U.239.236; 5.U.239.237; 5.U.239.238;5.U.239.239; 5.U.239.154; 5.U.239.157; 5.U.239.166; 5.U.239.169;5.U.239.172; 5.U.239.175; 5.U.239.240; 5.U.239.244; 5.U.154.228;5.U.154.229; 5.U.154.230; 5.U.154.231; 5.U.154.236; 5.U.154.237;5.U.154.238; 5.U.154.239; 5.U.154.154; 5.U.154.157; 5.U.154.166;5.U.154.169; 5.U.154.172; 5.U.154.175; 5.U.154.240; 5.U.154.244;5.U.157.228; 5.U.157.229; 5.U.157.230; 5.U.157.231; 5.U.157.236;5.U.157.237; 5.U.157.238; 5.U.157.239; 5.U.157.154; 5.U.157.157;5.U.157.166; 5.U.157.169; 5.U.157.172; 5.U.157.175; 5.U.157.240;5.U.157.244; 5.U.166.228; 5.U.166.229; 5.U.166.230; 5.U.166.231;5.U.166.236; 5.U.166.237; 5.U.166.238; 5.U.166.239; 5.U.166.154;5.U.166.157; 5.U.166.166; 5.U.166.169; 5.U.166.172; 5.U.166.175;5.U.166.240; 5.U.166.244; 5.U.169.228; 5.U.169.229; 5.U.169.230;5.U.169.231; 5.U.169.236; 5.U.169.237; 5.U.169.238; 5.U.169.239;5.U.169.154; 5.U.169.157; 5.U.169.166; 5.U.169.169; 5.U.169.172;5.U.169.175; 5.U.169.240; 5.U.169.244; 5.U.172.228; 5.U.172.229;5.U.172.230; 5.U.172.231; 5.U.172.236; 5.U.172.237; 5.U.172.238;5.U.172.239; 5.U.172.154; 5.U.172.157; 5.U.172.166; 5.U.172.169;5.U.172.172; 5.U.172.175; 5.U.172.240; 5.U.172.244; 5.U.175.228;5.U.175.229; 5.U.175.230; 5.U.175.231; 5.U.175.236; 5.U.175.237;5.U.175.238; 5.U.175.239; 5.U.175.154; 5.U.175.157; 5.U.175.166;5.U.175.169; 5.U.175.172; 5.U.175.175; 5.U.175.240; 5.U.175.244;5.U.240.228; 5.U.240.229; 5.U.240.230; 5.U.240.231; 5.U.240.236;5.U.240.237; 5.U.240.238; 5.U.240.239; 5.U.240.154; 5.U.240.157;5.U.240.166; 5.U.240.169; 5.U.240.172; 5.U.240.175; 5.U.240.240;5.U.240.244; 5.U.244.228; 5.U.244.229; 5.U.244.230; 5.U.244.231;5.U.244.236; 5.U.244.237; 5.U.244.238; 5.U.244.239; 5.U.244.154;5.U.244.157; 5.U.244.166; 5.U.244.169; 5.U.244.172; 5.U.244.175;5.U.244.240; 5.U.244.244; Prodrugs of 5.W 5.W.228.228; 5.W.228.229;5.W.228.230; 5.W.228.231; 5.W.228.236; 5.W.228.237; 5.W.228.238;5.W.228.239; 5.W.228.154; 5.W.228.157; 5.W.228.166; 5.W.228.169;5.W.228.172; 5.W.228.175; 5.W.228.240; 5.W.228.244; 5.W.229.228;5.W.229.229; 5.W.229.230; 5.W.229.231; 5.W.229.236; 5.W.229.237;5.W.229.238; 5.W.229.239; 5.W.229.154; 5.W.229.157; 5.W.229.166;5.W.229.169; 5.W.229.172; 5.W.229.175; 5.W.229.240; 5.W.229.244;5.W.230.228; 5.W.230.229; 5.W.230.230; 5.W.230.231; 5.W.230.236;5.W.230.237; 5.W.230.238; 5.W.230.239; 5.W.230.154; 5.W.230.157;5.W.230.166; 5.W.230.169; 5.W.230.172; 5.W.230.175; 5.W.230.240;5.W.230.244; 5.W.231.228; 5.W.231.229; 5.W.231.230; 5.W.231.231;5.W.231.236; 5.W.231.237; 5.W.231.238; 5.W.231.239; 5.W.231.154;5.W.231.157; 5.W.231.166; 5.W.231.169; 5.W.231.172; 5.W.231.175;5.W.231.240; 5.W.231.244; 5.W.236.228; 5.W.236.229; 5.W.236.230;5.W.236.231; 5.W.236.236; 5.W.236.237; 5.W.236.238; 5.W.236.239;5.W.236.154; 5.W.236.157; 5.W.236.166; 5.W.236.169; 5.W.236.172;5.W.236.175; 5.W.236.240; 5.W.236.244; 5.W.237.228; 5.W.237.229;5.W.237.230; 5.W.237.231; 5.W.237.236; 5.W.237.237; 5.W.237.238;5.W.237.239; 5.W.237.154; 5.W.237.157; 5.W.237.166; 5.W.237.169;5.W.237.172; 5.W.237.175; 5.W.237.240; 5.W.237.244; 5.W.238.228;5.W.238.229; 5.W.238.230; 5.W.238.231; 5.W.238.236; 5.W.238.237;5.W.238.238; 5.W.238.239; 5.W.238.154; 5.W.238.157; 5.W.238.166;5.W.238.169; 5.W.238.172; 5.W.238.175; 5.W.238.240; 5.W.238.244;5.W.239.228; 5.W.239.229; 5.W.239.230; 5.W.239.231; 5.W.239.236;5.W.239.237; 5.W.239.238; 5.W.239.239; 5.W.239.154; 5.W.239.157;5.W.239.166; 5.W.239.169; 5.W.239.172; 5.W.239.175; 5.W.239.240;5.W.239.244; 5.W.154.228; 5.W.154.229; 5.W.154.230; 5.W.154.231;5.W.154.236; 5.W.154.237; 5.W.154.238; 5.W.154.239; 5.W.154.154;5.W.154.157; 5.W.154.166; 5.W.154.169; 5.W.154.172; 5.W.154.175;5.W.154.240; 5.W.154.244; 5.W.157.228; 5.W.157.229; 5.W.157.230;5.W.157.231; 5.W.157.236; 5.W.157.237; 5.W.157.238; 5.W.157.239;5.W.157.154; 5.W.157.157; 5.W.157.166; 5.W.157.169; 5.W.157.172;5.W.157.175; 5.W.157.240; 5.W.157.244; 5.W.166.228; 5.W.166.229;5.W.166.230; 5.W.166.231; 5.W.166.236; 5.W.166.237; 5.W.166.238;5.W.166.239; 5.W.166.154; 5.W.166.157; 5.W.166.166; 5.W.166.169;5.W.166.172; 5.W.166.175; 5.W.166.240; 5.W.166.244; 5.W.169.228;5.W.169.229; 5.W.169.230; 5.W.169.231; 5.W.169.236; 5.W.169.237;5.W.169.238; 5.W.169.239; 5.W.169.154; 5.W.169.157; 5.W.169.166;5.W.169.169; 5.W.169.172; 5.W.169.175; 5.W.169.240; 5.W.169.244;5.W.172.228; 5.W.172.229; 5.W.172.230; 5.W.172.231; 5.W.172.236;5.W.172.237; 5.W.172.238; 5.W.172.239; 5.W.172.154; 5.W.172.157;5.W.172.166; 5.W.172.169; 5.W.172.172; 5.W.172.175; 5.W.172.240;5.W.172.244; 5.W.175.228; 5.W.175.229; 5.W.175.230; 5.W.175.231;5.W.175.236; 5.W.175.237; 5.W.175.238; 5.W.175.239; 5.W.175.154;5.W.175.157; 5.W.175.166; 5.W.175.169; 5.W.175.172; 5.W.175.175;5.W.175.240; 5.W.175.244; 5.W.240.228; 5.W.240.229; 5.W.240.230;5.W.240.231; 5.W.240.236; 5.W.240.237; 5.W.240.238; 5.W.240.239;5.W.240.154; 5.W.240.157; 5.W.240.166; 5.W.240.169; 5.W.240.172;5.W.240.175; 5.W.240.240; 5.W.240.244; 5.W.244.228; 5.W.244.229;5.W.244.230; 5.W.244.231; 5.W.244.236; 5.W.244.237; 5.W.244.238;5.W.244.239; 5.W.244.154; 5.W.244.157; 5.W.244.166; 5.W.244.169;5.W.244.172; 5.W.244.175; 5.W.244.240; 5.W.244.244; Prodrugs of 5.Y5.Y.228.228; 5.Y.228.229; 5.Y.228.230; 5.Y.228.231; 5.Y.228.236;5.Y.228.237; 5.Y.228.238; 5.Y.228.239; 5.Y.228.154; 5.Y.228.157;5.Y.228.166; 5.Y.228.169; 5.Y.228.172; 5.Y.228.175; 5.Y.228.240;5.Y.228.244; 5.Y.229.228; 5.Y.229.229; 5.Y.229.230; 5.Y.229.231;5.Y.229.236; 5.Y.229.237; 5.Y.229.238; 5.Y.229.239; 5.Y.229.154;5.Y.229.157; 5.Y.229.166; 5.Y.229.169; 5.Y.229.172; 5.Y.229.175;5.Y.229.240; 5.Y.229.244; 5.Y.230.228; 5.Y.230.229; 5.Y.230.230;5.Y.230.231; 5.Y.230.236; 5.Y.230.237; 5.Y.230.238; 5.Y.230.239;5.Y.230.154; 5.Y.230.157; 5.Y.230.166; 5.Y.230.169; 5.Y.230.172;5.Y.230.175; 5.Y.230.240; 5.Y.230.244; 5.Y.231.228; 5.Y.231.229;5.Y.231.230; 5.Y.231.231; 5.Y.231.236; 5.Y.231.237; 5.Y.231.238;5.Y.231.239; 5.Y.231.154; 5.Y.231.157; 5.Y.231.166; 5.Y.231.169;5.Y.231.172; 5.Y.231.175; 5.Y.231.240; 5.Y.231.244; 5.Y.236.228;5.Y.236.229; 5.Y.236.230; 5.Y.236.231; 5.Y.236.236; 5.Y.236.237;5.Y.236.238; 5.Y.236.239; 5.Y.236.154; 5.Y.236.157; 5.Y.236.166;5.Y.236.169; 5.Y.236.172; 5.Y.236.175; 5.Y.236.240; 5.Y.236.244;5.Y.237.228; 5.Y.237.229; 5.Y.237.230; 5.Y.237.231; 5.Y.237.236;5.Y.237.237; 5.Y.237.238; 5.Y.237.239; 5.Y.237.154; 5.Y.237.157;5.Y.237.166; 5.Y.237.169; 5.Y.237.172; 5.Y.237.175; 5.Y.237.240;5.Y.237.244; 5.Y.238.228; 5.Y.238.229; 5.Y.238.230; 5.Y.238.231;5.Y.238.236; 5.Y.238.237; 5.Y.238.238; 5.Y.238.239; 5.Y.238.154;5.Y.238.157; 5.Y.238.166; 5.Y.238.169; 5.Y.238.172; 5.Y.238.175;5.Y.238.240; 5.Y.238.244; 5.Y.239.228; 5.Y.239.229; 5.Y.239.230;5.Y.239.231; 5.Y.239.236; 5.Y.239.237; 5.Y.239.238; 5.Y.239.239;5.Y.239.154; 5.Y.239.157; 5.Y.239.166; 5.Y.239.169; 5.Y.239.172;5.Y.239.175; 5.Y.239.240; 5.Y.239.244; 5.Y.154.228; 5.Y.154.229;5.Y.154.230; 5.Y.154.231; 5.Y.154.236; 5.Y.154.237; 5.Y.154.238;5.Y.154.239; 5.Y.154.154; 5.Y.154.157; 5.Y.154.166; 5.Y.154.169;5.Y.154.172; 5.Y.154.175; 5.Y.154.240; 5.Y.154.244; 5.Y.157.228;5.Y.157.229; 5.Y.157.230; 5.Y.157.231; 5.Y.157.236; 5.Y.157.237;5.Y.157.238; 5.Y.157.239; 5.Y.157.154; 5.Y.157.157; 5.Y.157.166;5.Y.157.169; 5.Y.157.172; 5.Y.157.175; 5.Y.157.240; 5.Y.157.244;5.Y.166.228; 5.Y.166.229; 5.Y.166.230; 5.Y.166.231; 5.Y.166.236;5.Y.166.237; 5.Y.166.238; 5.Y.166.239; 5.Y.166.154; 5.Y.166.157;5.Y.166.166; 5.Y.166.169; 5.Y.166.172; 5.Y.166.175; 5.Y.166.240;5.Y.166.244; 5.Y.169.228; 5.Y.169.229; 5.Y.169.230; 5.Y.169.231;5.Y.169.236; 5.Y.169.237; 5.Y.169.238; 5.Y.169.239; 5.Y.169.154;5.Y.169.157; 5.Y.169.166; 5.Y.169.169; 5.Y.169.172; 5.Y.169.175;5.Y.169.240; 5.Y.169.244; 5.Y.172.228; 5.Y.172.229; 5.Y.172.230;5.Y.172.231; 5.Y.172.236; 5.Y.172.237; 5.Y.172.238; 5.Y.172.239;5.Y.172.154; 5.Y.172.157; 5.Y.172.166; 5.Y.172.169; 5.Y.172.172;5.Y.172.175; 5.Y.172.240; 5.Y.172.244; 5.Y.175.228; 5.Y.175.229;5.Y.175.230; 5.Y.175.231; 5.Y.175.236; 5.Y.175.237; 5.Y.175.238;5.Y.175.239; 5.Y.175.154; 5.Y.175.157; 5.Y.175.166; 5.Y.175.169;5.Y.175.172; 5.Y.175.175; 5.Y.175.240; 5.Y.175.244; 5.Y.240.228;5.Y.240.229; 5.Y.240.230; 5.Y.240.231; 5.Y.240.236; 5.Y.240.237;5.Y.240.238; 5.Y.240.239; 5.Y.240.154; 5.Y.240.157; 5.Y.240.166;5.Y.240.169; 5.Y.240.172; 5.Y.240.175; 5.Y.240.240; 5.Y.240.244;5.Y.244.228; 5.Y.244.229; 5.Y.244.230; 5.Y.244.231; 5.Y.244.236;5.Y.244.237; 5.Y.244.238; 5.Y.244.239; 5.Y.244.154; 5.Y.244.157;5.Y.244.166; 5.Y.244.169; 5.Y.244.172; 5.Y.244.175; 5.Y.244.240;5.Y.244.244; Prodrugs of 6.B 6.B.228.228; 6.B.228.229; 6.B.228.230;6.B.228.231; 6.B.228.236; 6.B.228.237; 6.B.228.238; 6.B.228.239;6.B.228.154; 6.B.228.157; 6.B.228.166; 6.B.228.169; 6.B.228.172;6.B.228.175; 6.B.228.240; 6.B.228.244; 6.B.229.228; 6.B.229.229;6.B.229.230; 6.B.229.231; 6.B.229.236; 6.B.229.237; 6.B.229.238;6.B.229.239; 6.B.229.154; 6.B.229.157; 6.B.229.166; 6.B.229.169;6.B.229.172; 6.B.229.175; 6.B.229.240; 6.B.229.244; 6.B.230.228;6.B.230.229; 6.B.230.230; 6.B.230.231; 6.B.230.236; 6.B.230.237;6.B.230.238; 6.B.230.239; 6.B.230.154; 6.B.230.157; 6.B.230.166;6.B.230.169; 6.B.230.172; 6.B.230.175; 6.B.230.240; 6.B.230.244;6.B.231.228; 6.B.231.229; 6.B.231.230; 6.B.231.231; 6.B.231.236;6.B.231.237; 6.B.231.238; 6.B.231.239; 6.B.231.154; 6.B.231.157;6.B.231.166; 6.B.231.169; 6.B.231.172; 6.B.231.175; 6.B.231.240;6.B.231.244; 6.B.236.228; 6.B.236.229; 6.B.236.230; 6.B.236.231;6.B.236.236; 6.B.236.237; 6.B.236.238; 6.B.236.239; 6.B.236.154;6.B.236.157; 6.B.236.166; 6.B.236.169; 6.B.236.172; 6.B.236.175;6.B.236.240; 6.B.236.244; 6.B.237.228; 6.B.237.229; 6.B.237.230;6.B.237.231; 6.B.237.236; 6.B.237.237; 6.B.237.238; 6.B.237.239;6.B.237.154; 6.B.237.157; 6.B.237.166; 6.B.237.169; 6.B.237.172;6.B.237.175; 6.B.237.240; 6.B.237.244; 6.B.238.228; 6.B.238.229;6.B.238.230; 6.B.238.231; 6.B.238.236; 6.B.238.237; 6.B.238.238;6.B.238.239; 6.B.238.154; 6.B.238.157; 6.B.238.166; 6.B.238.169;6.B.238.172; 6.B.238.175; 6.B.238.240; 6.B.238.244; 6.B.239.228;6.B.239.229; 6.B.239.230; 6.B.239.231; 6.B.239.236; 6.B.239.237;6.B.239.238; 6.B.239.239; 6.B.239.154; 6.B.239.157; 6.B.239.166;6.B.239.169; 6.B.239.172; 6.B.239.175; 6.B.239.240; 6.B.239.244;6.B.154.228; 6.B.154.229; 6.B.154.230; 6.B.154.231; 6.B.154.236;6.B.154.237; 6.B.154.238; 6.B.154.239; 6.B.154.154; 6.B.154.157;6.B.154.166; 6.B.154.169; 6.B.154.172; 6.B.154.175; 6.B.154.240;6.B.154.244; 6.B.157.228; 6.B.157.229; 6.B.157.230; 6.B.157.231;6.B.157.236; 6.B.157.237; 6.B.157.238; 6.B.157.239; 6.B.157.154;6.B.157.157; 6.B.157.166; 6.B.157.169; 6.B.157.172; 6.B.157.175;6.B.157.240; 6.B.157.244; 6.B.166.228; 6.B.166.229; 6.B.166.230;6.B.166.231; 6.B.166.236; 6.B.166.237; 6.B.166.238; 6.B.166.239;6.B.166.154; 6.B.166.157; 6.B.166.166; 6.B.166.169; 6.B.166.172;6.B.166.175; 6.B.166.240; 6.B.166.244; 6.B.169.228; 6.B.169.229;6.B.169.230; 6.B.169.231; 6.B.169.236; 6.B.169.237; 6.B.169.238;6.B.169.239; 6.B.169.154; 6.B.169.157; 6.B.169.166; 6.B.169.169;6.B.169.172; 6.B.169.175; 6.B.169.240; 6.B.169.244; 6.B.172.228;6.B.172.229; 6.B.172.230; 6.B.172.231; 6.B.172.236; 6.B.172.237;6.B.172.238; 6.B.172.239; 6.B.172.154; 6.B.172.157; 6.B.172.166;6.B.172.169; 6.B.172.172; 6.B.172.175; 6.B.172.240; 6.B.172.244;6.B.175.228; 6.B.175.229; 6.B.175.230; 6.B.175.231; 6.B.175.236;6.B.175.237; 6.B.175.238; 6.B.175.239; 6.B.175.154; 6.B.175.157;6.B.175.166; 6.B.175.169; 6.B.175.172; 6.B.175.175; 6.B.175.240;6.B.175.244; 6.B.240.228; 6.B.240.229; 6.B.240.230; 6.B.240.231;6.B.240.236; 6.B.240.237; 6.B.240.238; 6.B.240.239; 6.B.240.154;6.B.240.157; 6.B.240.166; 6.B.240.169; 6.B.240.172; 6.B.240.175;6.B.240.240; 6.B.240.244; 6.B.244.228; 6.B.244.229; 6.B.244.230;6.B.244.231; 6.B.244.236; 6.B.244.237; 6.B.244.238; 6.B.244.239;6.B.244.154; 6.B.244.157; 6.B.244.166; 6.B.244.169; 6.B.244.172;6.B.244.175; 6.B.244.240; 6.B.244.244; Prodrugs of 6.D 6.D.228.228;6.D.228.229; 6.D.228.230; 6.D.228.231; 6.D.228.236; 6.D.228.237;6.D.228.238; 6.D.228.239; 6.D.228.154; 6.D.228.157; 6.D.228.166;6.D.228.169; 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6.D.244.172; 6.D.244.175; 6.D.244.240; 6.D.244.244;Prodrugs of 6.E 6.E.228.228; 6.E.228.229; 6.E.228.230; 6.E.228.231;6.E.228.236; 6.E.228.237; 6.E.228.238; 6.E.228.239; 6.E.228.154;6.E.228.157; 6.E.228.166; 6.E.228.169; 6.E.228.172; 6.E.228.175;6.E.228.240; 6.E.228.244; 6.E.229.228; 6.E.229.229; 6.E.229.230;6.E.229.231; 6.E.229.236; 6.E.229.237; 6.E.229.238; 6.E.229.239;6.E.229.154; 6.E.229.157; 6.E.229.166; 6.E.229.169; 6.E.229.172;6.E.229.175; 6.E.229.240; 6.E.229.244; 6.E.230.228; 6.E.230.229;6.E.230.230; 6.E.230.231; 6.E.230.236; 6.E.230.237; 6.E.230.238;6.E.230.239; 6.E.230.154; 6.E.230.157; 6.E.230.166; 6.E.230.169;6.E.230.172; 6.E.230.175; 6.E.230.240; 6.E.230.244; 6.E.231.228;6.E.231.229; 6.E.231.230; 6.E.231.231; 6.E.231.236; 6.E.231.237;6.E.231.238; 6.E.231.239; 6.E.231.154; 6.E.231.157; 6.E.231.166;6.E.231.169; 6.E.231.172; 6.E.231.175; 6.E.231.240; 6.E.231.244;6.E.236.228; 6.E.236.229; 6.E.236.230; 6.E.236.231; 6.E.236.236;6.E.236.237; 6.E.236.238; 6.E.236.239; 6.E.236.154; 6.E.236.157;6.E.236.166; 6.E.236.169; 6.E.236.172; 6.E.236.175; 6.E.236.240;6.E.236.244; 6.E.237.228; 6.E.237.229; 6.E.237.230; 6.E.237.231;6.E.237.236; 6.E.237.237; 6.E.237.238; 6.E.237.239; 6.E.237.154;6.E.237.157; 6.E.237.166; 6.E.237.169; 6.E.237.172; 6.E.237.175;6.E.237.240; 6.E.237.244; 6.E.238.228; 6.E.238.229; 6.E.238.230;6.E.238.231; 6.E.238.236; 6.E.238.237; 6.E.238.238; 6.E.238.239;6.E.238.154; 6.E.238.157; 6.E.238.166; 6.E.238.169; 6.E.238.172;6.E.238.175; 6.E.238.240; 6.E.238.244; 6.E.239.228; 6.E.239.229;6.E.239.230; 6.E.239.231; 6.E.239.236; 6.E.239.237; 6.E.239.238;6.E.239.239; 6.E.239.154; 6.E.239.157; 6.E.239.166; 6.E.239.169;6.E.239.172; 6.E.239.175; 6.E.239.240; 6.E.239.244; 6.E.154.228;6.E.154.229; 6.E.154.230; 6.E.154.231; 6.E.154.236; 6.E.154.237;6.E.154.238; 6.E.154.239; 6.E.154.154; 6.E.154.157; 6.E.154.166;6.E.154.169; 6.E.154.172; 6.E.154.175; 6.E.154.240; 6.E.154.244;6.E.157.228; 6.E.157.229; 6.E.157.230; 6.E.157.231; 6.E.157.236;6.E.157.237; 6.E.157.238; 6.E.157.239; 6.E.157.154; 6.E.157.157;6.E.157.166; 6.E.157.169; 6.E.157.172; 6.E.157.175; 6.E.157.240;6.E.157.244; 6.E.166.228; 6.E.166.229; 6.E.166.230; 6.E.166.231;6.E.166.236; 6.E.166.237; 6.E.166.238; 6.E.166.239; 6.E.166.154;6.E.166.157; 6.E.166.166; 6.E.166.169; 6.E.166.172; 6.E.166.175;6.E.166.240; 6.E.166.244; 6.E.169.228; 6.E.169.229; 6.E.169.230;6.E.169.231; 6.E.169.236; 6.E.169.237; 6.E.169.238; 6.E.169.239;6.E.169.154; 6.E.169.157; 6.E.169.166; 6.E.169.169; 6.E.169.172;6.E.169.175; 6.E.169.240; 6.E.169.244; 6.E.172.228; 6.E.172.229;6.E.172.230; 6.E.172.231; 6.E.172.236; 6.E.172.237; 6.E.172.238;6.E.172.239; 6.E.172.154; 6.E.172.157; 6.E.172.166; 6.E.172.169;6.E.172.172; 6.E.172.175; 6.E.172.240; 6.E.172.244; 6.E.175.228;6.E.175.229; 6.E.175.230; 6.E.175.231; 6.E.175.236; 6.E.175.237;6.E.175.238; 6.E.175.239; 6.E.175.154; 6.E.175.157; 6.E.175.166;6.E.175.169; 6.E.175.172; 6.E.175.175; 6.E.175.240; 6.E.175.244;6.E.240.228; 6.E.240.229; 6.E.240.230; 6.E.240.231; 6.E.240.236;6.E.240.237; 6.E.240.238; 6.E.240.239; 6.E.240.154; 6.E.240.157;6.E.240.166; 6.E.240.169; 6.E.240.172; 6.E.240.175; 6.E.240.240;6.E.240.244; 6.E.244.228; 6.E.244.229; 6.E.244.230; 6.E.244.231;6.E.244.236; 6.E.244.237; 6.E.244.238; 6.E.244.239; 6.E.244.154;6.E.244.157; 6.E.244.166; 6.E.244.169; 6.E.244.172; 6.E.244.175;6.E.244.240; 6.E.244.244; Prodrugs of 6.G 6.G.228.228; 6.G.228.229;6.G.228.230; 6.G.228.231; 6.G.228.236; 6.G.228.237; 6.G.228.238;6.G.228.239; 6.G.228.154; 6.G.228.157; 6.G.228.166; 6.G.228.169;6.G.228.172; 6.G.228.175; 6.G.228.240; 6.G.228.244; 6.G.229.228;6.G.229.229; 6.G.229.230; 6.G.229.231; 6.G.229.236; 6.G.229.237;6.G.229.238; 6.G.229.239; 6.G.229.154; 6.G.229.157; 6.G.229.166;6.G.229.169; 6.G.229.172; 6.G.229.175; 6.G.229.240; 6.G.229.244;6.G.230.228; 6.G.230.229; 6.G.230.230; 6.G.230.231; 6.G.230.236;6.G.230.237; 6.G.230.238; 6.G.230.239; 6.G.230.154; 6.G.230.157;6.G.230.166; 6.G.230.169; 6.G.230.172; 6.G.230.175; 6.G.230.240;6.G.230.244; 6.G.231.228; 6.G.231.229; 6.G.231.230; 6.G.231.231;6.G.231.236; 6.G.231.237; 6.G.231.238; 6.G.231.239; 6.G.231.154;6.G.231.157; 6.G.231.166; 6.G.231.169; 6.G.231.172; 6.G.231.175;6.G.231.240; 6.G.231.244; 6.G.236.228; 6.G.236.229; 6.G.236.230;6.G.236.231; 6.G.236.236; 6.G.236.237; 6.G.236.238; 6.G.236.239;6.G.236.154; 6.G.236.157; 6.G.236.166; 6.G.236.169; 6.G.236.172;6.G.236.175; 6.G.236.240; 6.G.236.244; 6.G.237.228; 6.G.237.229;6.G.237.230; 6.G.237.231; 6.G.237.236; 6.G.237.237; 6.G.237.238;6.G.237.239; 6.G.237.154; 6.G.237.157; 6.G.237.166; 6.G.237.169;6.G.237.172; 6.G.237.175; 6.G.237.240; 6.G.237.244; 6.G.238.228;6.G.238.229; 6.G.238.230; 6.G.238.231; 6.G.238.236; 6.G.238.237;6.G.238.238; 6.G.238.239; 6.G.238.154; 6.G.238.157; 6.G.238.166;6.G.238.169; 6.G.238.172; 6.G.238.175; 6.G.238.240; 6.G.238.244;6.G.239.228; 6.G.239.229; 6.G.239.230; 6.G.239.231; 6.G.239.236;6.G.239.237; 6.G.239.238; 6.G.239.239; 6.G.239.154; 6.G.239.157;6.G.239.166; 6.G.239.169; 6.G.239.172; 6.G.239.175; 6.G.239.240;6.G.239.244; 6.G.154.228; 6.G.154.229; 6.G.154.230; 6.G.154.231;6.G.154.236; 6.G.154.237; 6.G.154.238; 6.G.154.239; 6.G.154.154;6.G.154.157; 6.G.154.166; 6.G.154.169; 6.G.154.172; 6.G.154.175;6.G.154.240; 6.G.154.244; 6.G.157.228; 6.G.157.229; 6.G.157.230;6.G.157.231; 6.G.157.236; 6.G.157.237; 6.G.157.238; 6.G.157.239;6.G.157.154; 6.G.157.157; 6.G.157.166; 6.G.157.169; 6.G.157.172;6.G.157.175; 6.G.157.240; 6.G.157.244; 6.G.166.228; 6.G.166.229;6.G.166.230; 6.G.166.231; 6.G.166.236; 6.G.166.237; 6.G.166.238;6.G.166.239; 6.G.166.154; 6.G.166.157; 6.G.166.166; 6.G.166.169;6.G.166.172; 6.G.166.175; 6.G.166.240; 6.G.166.244; 6.G.169.228;6.G.169.229; 6.G.169.230; 6.G.169.231; 6.G.169.236; 6.G.169.237;6.G.169.238; 6.G.169.239; 6.G.169.154; 6.G.169.157; 6.G.169.166;6.G.169.169; 6.G.169.172; 6.G.169.175; 6.G.169.240; 6.G.169.244;6.G.172.228; 6.G.172.229; 6.G.172.230; 6.G.172.231; 6.G.172.236;6.G.172.237; 6.G.172.238; 6.G.172.239; 6.G.172.154; 6.G.172.157;6.G.172.166; 6.G.172.169; 6.G.172.172; 6.G.172.175; 6.G.172.240;6.G.172.244; 6.G.175.228; 6.G.175.229; 6.G.175.230; 6.G.175.231;6.G.175.236; 6.G.175.237; 6.G.175.238; 6.G.175.239; 6.G.175.154;6.G.175.157; 6.G.175.166; 6.G.175.169; 6.G.175.172; 6.G.175.175;6.G.175.240; 6.G.175.244; 6.G.240.228; 6.G.240.229; 6.G.240.230;6.G.240.231; 6.G.240.236; 6.G.240.237; 6.G.240.238; 6.G.240.239;6.G.240.154; 6.G.240.157; 6.G.240.166; 6.G.240.169; 6.G.240.172;6.G.240.175; 6.G.240.240; 6.G.240.244; 6.G.244.228; 6.G.244.229;6.G.244.230; 6.G.244.231; 6.G.244.236; 6.G.244.237; 6.G.244.238;6.G.244.239; 6.G.244.154; 6.G.244.157; 6.G.244.166; 6.G.244.169;6.G.244.172; 6.G.244.175; 6.G.244.240; 6.G.244.244; Prodrugs of 6.I6.I.228.228; 6.I.228.229; 6.I.228.230; 6.I.228.231; 6.I.228.236;6.I.228.237; 6.I.228.238; 6.I.228.239; 6.I.228.154; 6.I.228.157;6.I.228.166; 6.I.228.169; 6.I.228.172; 6.I.228.175; 6.I.228.240;6.I.228.244; 6.I.229.228; 6.I.229.229; 6.I.229.230; 6.I.229.231;6.I.229.236; 6.I.229.237; 6.I.229.238; 6.I.229.239; 6.I.229.154;6.I.229.157; 6.I.229.166; 6.I.229.169; 6.I.229.172; 6.I.229.175;6.I.229.240; 6.I.229.244; 6.I.230.228; 6.I.230.229; 6.I.230.230;6.I.230.231; 6.I.230.236; 6.I.230.237; 6.I.230.238; 6.I.230.239;6.I.230.154; 6.I.230.157; 6.I.230.166; 6.I.230.169; 6.I.230.172;6.I.230.175; 6.I.230.240; 6.I.230.244; 6.I.231.228; 6.I.231.229;6.I.231.230; 6.I.231.231; 6.I.231.236; 6.I.231.237; 6.I.231.238;6.I.231.239; 6.I.231.154; 6.I.231.157; 6.I.231.166; 6.I.231.169;6.I.231.172; 6.I.231.175; 6.I.231.240; 6.I.231.244; 6.I.236.228;6.I.236.229; 6.I.236.230; 6.I.236.231; 6.I.236.236; 6.I.236.237;6.I.236.238; 6.I.236.239; 6.I.236.154; 6.I.236.157; 6.I.236.166;6.I.236.169; 6.I.236.172; 6.I.236.175; 6.I.236.240; 6.I.236.244;6.I.237.228; 6.I.237.229; 6.I.237.230; 6.I.237.231; 6.I.237.236;6.I.237.237; 6.I.237.238; 6.I.237.239; 6.I.237.154; 6.I.237.157;6.I.237.166; 6.I.237.169; 6.I.237.172; 6.I.237.175; 6.I.237.240;6.I.237.244; 6.I.238.228; 6.I.238.229; 6.I.238.230; 6.I.238.231;6.I.238.236; 6.I.238.237; 6.I.238.238; 6.I.238.239; 6.I.238.154;6.I.238.157; 6.I.238.166; 6.I.238.169; 6.I.238.172; 6.I.238.175;6.I.238.240; 6.I.238.244; 6.I.239.228; 6.I.239.229; 6.I.239.230;6.I.239.231; 6.I.239.236; 6.I.239.237; 6.I.239.238; 6.I.239.239;6.I.239.154; 6.I.239.157; 6.I.239.166; 6.I.239.169; 6.I.239.172;6.I.239.175; 6.I.239.240; 6.I.239.244; 6.I.154.228; 6.I.154.229;6.I.154.230; 6.I.154.231; 6.I.154.236; 6.I.154.237; 6.I.154.238;6.I.154.239; 6.I.154.154; 6.I.154.157; 6.I.154.166; 6.I.154.169;6.I.154.172; 6.I.154.175; 6.I.154.240; 6.I.154.244; 6.I.157.228;6.I.157.229; 6.I.157.230; 6.I.157.231; 6.I.157.236; 6.I.157.237;6.I.157.238; 6.I.157.239; 6.I.157.154; 6.I.157.157; 6.I.157.166;6.I.157.169; 6.I.157.172; 6.I.157.175; 6.I.157.240; 6.I.157.244;6.I.166.228; 6.I.166.229; 6.I.166.230; 6.I.166.231; 6.I.166.236;6.I.166.237; 6.I.166.238; 6.I.166.239; 6.I.166.154; 6.I.166.157;6.I.166.166; 6.I.166.169; 6.I.166.172; 6.I.166.175; 6.I.166.240;6.I.166.244; 6.I.169.228; 6.I.169.229; 6.I.169.230; 6.I.169.231;6.I.169.236; 6.I.169.237; 6.I.169.238; 6.I.169.239; 6.I.169.154;6.I.169.157; 6.I.169.166; 6.I.169.169; 6.I.169.172; 6.I.169.175;6.I.169.240; 6.I.169.244; 6.I.172.228; 6.I.172.229; 6.I.172.230;6.I.172.231; 6.I.172.236; 6.I.172.237; 6.I.172.238; 6.I.172.239;6.I.172.154; 6.I.172.157; 6.I.172.166; 6.I.172.169; 6.I.172.172;6.I.172.175; 6.I.172.240; 6.I.172.244; 6.I.175.228; 6.I.175.229;6.I.175.230; 6.I.175.231; 6.I.175.236; 6.I.175.237; 6.I.175.238;6.I.175.239; 6.I.175.154; 6.I.175.157; 6.I.175.166; 6.I.175.169;6.I.175.172; 6.I.175.175; 6.I.175.240; 6.I.175.244; 6.I.240.228;6.I.240.229; 6.I.240.230; 6.I.240.231; 6.I.240.236; 6.I.240.237;6.I.240.238; 6.I.240.239; 6.I.240.154; 6.I.240.157; 6.I.240.166;6.I.240.169; 6.I.240.172; 6.I.240.175; 6.I.240.240; 6.I.240.244;6.I.244.228; 6.I.244.229; 6.I.244.230; 6.I.244.231; 6.I.244.236;6.I.244.237; 6.I.244.238; 6.I.244.239; 6.I.244.154; 6.I.244.157;6.I.244.166; 6.I.244.169; 6.I.244.172; 6.I.244.175; 6.I.244.240;6.I.244.244; Prodrugs of 6.J 6.J.228.228; 6.J.228.229; 6.J.228.230;6.J.228.231; 6.J.228.236; 6.J.228.237; 6.J.228.238; 6.J.228.239;6.J.228.154; 6.J.228.157; 6.J.228.166; 6.J.228.169; 6.J.228.172;6.J.228.175; 6.J.228.240; 6.J.228.244; 6.J.229.228; 6.J.229.229;6.J.229.230; 6.J.229.231; 6.J.229.236; 6.J.229.237; 6.J.229.238;6.J.229.239; 6.J.229.154; 6.J.229.157; 6.J.229.166; 6.J.229.169;6.J.229.172; 6.J.229.175; 6.J.229.240; 6.J.229.244; 6.J.230.228;6.J.230.229; 6.J.230.230; 6.J.230.231; 6.J.230.236; 6.J.230.237;6.J.230.238; 6.J.230.239; 6.J.230.154; 6.J.230.157; 6.J.230.166;6.J.230.169; 6.J.230.172; 6.J.230.175; 6.J.230.240; 6.J.230.244;6.J.231.228; 6.J.231.229; 6.J.231.230; 6.J.231.231; 6.J.231.236;6.J.231.237; 6.J.231.238; 6.J.231.239; 6.J.231.154; 6.J.231.157;6.J.231.166; 6.J.231.169; 6.J.231.172; 6.J.231.175; 6.J.231.240;6.J.231.244; 6.J.236.228; 6.J.236.229; 6.J.236.230; 6.J.236.231;6.J.236.236; 6.J.236.237; 6.J.236.238; 6.J.236.239; 6.J.236.154;6.J.236.157; 6.J.236.166; 6.J.236.169; 6.J.236.172; 6.J.236.175;6.J.236.240; 6.J.236.244; 6.J.237.228; 6.J.237.229; 6.J.237.230;6.J.237.231; 6.J.237.236; 6.J.237.237; 6.J.237.238; 6.J.237.239;6.J.237.154; 6.J.237.157; 6.J.237.166; 6.J.237.169; 6.J.237.172;6.J.237.175; 6.J.237.240; 6.J.237.244; 6.J.238.228; 6.J.238.229;6.J.238.230; 6.J.238.231; 6.J.238.236; 6.J.238.237; 6.J.238.238;6.J.238.239; 6.J.238.154; 6.J.238.157; 6.J.238.166; 6.J.238.169;6.J.238.172; 6.J.238.175; 6.J.238.240; 6.J.238.244; 6.J.239.228;6.J.239.229; 6.J.239.230; 6.J.239.231; 6.J.239.236; 6.J.239.237;6.J.239.238; 6.J.239.239; 6.J.239.154; 6.J.239.157; 6.J.239.166;6.J.239.169; 6.J.239.172; 6.J.239.175; 6.J.239.240; 6.J.239.244;6.J.154.228; 6.J.154.229; 6.J.154.230; 6.J.154.231; 6.J.154.236;6.J.154.237; 6.J.154.238; 6.J.154.239; 6.J.154.154; 6.J.154.157;6.J.154.166; 6.J.154.169; 6.J.154.172; 6.J.154.175; 6.J.154.240;6.J.154.244; 6.J.157.228; 6.J.157.229; 6.J.157.230; 6.J.157.231;6.J.157.236; 6.J.157.237; 6.J.157.238; 6.J.157.239; 6.J.157.154;6.J.157.157; 6.J.157.166; 6.J.157.169; 6.J.157.172; 6.J.157.175;6.J.157.240; 6.J.157.244; 6.J.166.228; 6.J.166.229; 6.J.166.230;6.J.166.231; 6.J.166.236; 6.J.166.237; 6.J.166.238; 6.J.166.239;6.J.166.154; 6.J.166.157; 6.J.166.166; 6.J.166.169; 6.J.166.172;6.J.166.175; 6.J.166.240; 6.J.166.244; 6.J.169.228; 6.J.169.229;6.J.169.230; 6.J.169.231; 6.J.169.236; 6.J.169.237; 6.J.169.238;6.J.169.239; 6.J.169.154; 6.J.169.157; 6.J.169.166; 6.J.169.169;6.J.169.172; 6.J.169.175; 6.J.169.240; 6.J.169.244; 6.J.172.228;6.J.172.229; 6.J.172.230; 6.J.172.231; 6.J.172.236; 6.J.172.237;6.J.172.238; 6.J.172.239; 6.J.172.154; 6.J.172.157; 6.J.172.166;6.J.172.169; 6.J.172.172; 6.J.172.175; 6.J.172.240; 6.J.172.244;6.J.175.228; 6.J.175.229; 6.J.175.230; 6.J.175.231; 6.J.175.236;6.J.175.237; 6.J.175.238; 6.J.175.239; 6.J.175.154; 6.J.175.157;6.J.175.166; 6.J.175.169; 6.J.175.172; 6.J.175.175; 6.J.175.240;6.J.175.244; 6.J.240.228; 6.J.240.229; 6.J.240.230; 6.J.240.231;6.J.240.236; 6.J.240.237; 6.J.240.238; 6.J.240.239; 6.J.240.154;6.J.240.157; 6.J.240.166; 6.J.240.169; 6.J.240.172; 6.J.240.175;6.J.240.240; 6.J.240.244; 6.J.244.228; 6.J.244.229; 6.J.244.230;6.J.244.231; 6.J.244.236; 6.J.244.237; 6.J.244.238; 6.J.244.239;6.J.244.154; 6.J.244.157; 6.J.244.166; 6.J.244.169; 6.J.244.172;6.J.244.175; 6.J.244.240; 6.J.244.244; Prodrugs of 6.L 6.L.228.228;6.L.228.229; 6.L.228.230; 6.L.228.231; 6.L.228.236; 6.L.228.237;6.L.228.238; 6.L.228.239; 6.L.228.154; 6.L.228.157; 6.L.228.166;6.L.228.169; 6.L.228.172; 6.L.228.175; 6.L.228.240; 6.L.228.244;6.L.229.228; 6.L.229.229; 6.L.229.230; 6.L.229.231; 6.L.229.236;6.L.229.237; 6.L.229.238; 6.L.229.239; 6.L.229.154; 6.L.229.157;6.L.229.166; 6.L.229.169; 6.L.229.172; 6.L.229.175; 6.L.229.240;6.L.229.244; 6.L.230.228; 6.L.230.229; 6.L.230.230; 6.L.230.231;6.L.230.236; 6.L.230.237; 6.L.230.238; 6.L.230.239; 6.L.230.154;6.L.230.157; 6.L.230.166; 6.L.230.169; 6.L.230.172; 6.L.230.175;6.L.230.240; 6.L.230.244; 6.L.231.228; 6.L.231.229; 6.L.231.230;6.L.231.231; 6.L.231.236; 6.L.231.237; 6.L.231.238; 6.L.231.239;6.L.231.154; 6.L.231.157; 6.L.231.166; 6.L.231.169; 6.L.231.172;6.L.231.175; 6.L.231.240; 6.L.231.244; 6.L.236.228; 6.L.236.229;6.L.236.230; 6.L.236.231; 6.L.236.236; 6.L.236.237; 6.L.236.238;6.L.236.239; 6.L.236.154; 6.L.236.157; 6.L.236.166; 6.L.236.169;6.L.236.172; 6.L.236.175; 6.L.236.240; 6.L.236.244; 6.L.237.228;6.L.237.229; 6.L.237.230; 6.L.237.231; 6.L.237.236; 6.L.237.237;6.L.237.238; 6.L.237.239; 6.L.237.154; 6.L.237.157; 6.L.237.166;6.L.237.169; 6.L.237.172; 6.L.237.175; 6.L.237.240; 6.L.237.244;6.L.238.228; 6.L.238.229; 6.L.238.230; 6.L.238.231; 6.L.238.236;6.L.238.237; 6.L.238.238; 6.L.238.239; 6.L.238.154; 6.L.238.157;6.L.238.166; 6.L.238.169; 6.L.238.172; 6.L.238.175; 6.L.238.240;6.L.238.244; 6.L.239.228; 6.L.239.229; 6.L.239.230; 6.L.239.231;6.L.239.236; 6.L.239.237; 6.L.239.238; 6.L.239.239; 6.L.239.154;6.L.239.157; 6.L.239.166; 6.L.239.169; 6.L.239.172; 6.L.239.175;6.L.239.240; 6.L.239.244; 6.L.154.228; 6.L.154.229; 6.L.154.230;6.L.154.231; 6.L.154.236; 6.L.154.237; 6.L.154.238; 6.L.154.239;6.L.154.154; 6.L.154.157; 6.L.154.166; 6.L.154.169; 6.L.154.172;6.L.154.175; 6.L.154.240; 6.L.154.244; 6.L.157.228; 6.L.157.229;6.L.157.230; 6.L.157.231; 6.L.157.236; 6.L.157.237; 6.L.157.238;6.L.157.239; 6.L.157.154; 6.L.157.157; 6.L.157.166; 6.L.157.169;6.L.157.172; 6.L.157.175; 6.L.157.240; 6.L.157.244; 6.L.166.228;6.L.166.229; 6.L.166.230; 6.L.166.231; 6.L.166.236; 6.L.166.237;6.L.166.238; 6.L.166.239; 6.L.166.154; 6.L.166.157; 6.L.166.166;6.L.166.169; 6.L.166.172; 6.L.166.175; 6.L.166.240; 6.L.166.244;6.L.169.228; 6.L.169.229; 6.L.169.230; 6.L.169.231; 6.L.169.236;6.L.169.237; 6.L.169.238; 6.L.169.239; 6.L.169.154; 6.L.169.157;6.L.169.166; 6.L.169.169; 6.L.169.172; 6.L.169.175; 6.L.169.240;6.L.169.244; 6.L.172.228; 6.L.172.229; 6.L.172.230; 6.L.172.231;6.L.172.236; 6.L.172.237; 6.L.172.238; 6.L.172.239; 6.L.172.154;6.L.172.157; 6.L.172.166; 6.L.172.169; 6.L.172.172; 6.L.172.175;6.L.172.240; 6.L.172.244; 6.L.175.228; 6.L.175.229; 6.L.175.230;6.L.175.231; 6.L.175.236; 6.L.175.237; 6.L.175.238; 6.L.175.239;6.L.175.154; 6.L.175.157; 6.L.175.166; 6.L.175.169; 6.L.175.172;6.L.175.175; 6.L.175.240; 6.L.175.244; 6.L.240.228; 6.L.240.229;6.L.240.230; 6.L.240.231; 6.L.240.236; 6.L.240.237; 6.L.240.238;6.L.240.239; 6.L.240.154; 6.L.240.157; 6.L.240.166; 6.L.240.169;6.L.240.172; 6.L.240.175; 6.L.240.240; 6.L.240.244; 6.L.244.228;6.L.244.229; 6.L.244.230; 6.L.244.231; 6.L.244.236; 6.L.244.237;6.L.244.238; 6.L.244.239; 6.L.244.154; 6.L.244.157; 6.L.244.166;6.L.244.169; 6.L.244.172; 6.L.244.175; 6.L.244.240; 6.L.244.244;Prodrugs of 6.O 6.O.228.228; 6.O.228.229; 6.O.228.230; 6.O.228.231;6.O.228.236; 6.O.228.237; 6.O.228.238; 6.O.228.239; 6.O.228.154;6.O.228.157; 6.O.228.166; 6.O.228.169; 6.O.228.172; 6.O.228.175;6.O.228.240; 6.O.228.244; 6.O.229.228; 6.O.229.229; 6.O.229.230;6.O.229.231; 6.O.229.236; 6.O.229.237; 6.O.229.238; 6.O.229.239;6.O.229.154; 6.O.229.157; 6.O.229.166; 6.O.229.169; 6.O.229.172;6.O.229.175; 6.O.229.240; 6.O.229.244; 6.O.230.228; 6.O.230.229;6.O.230.230; 6.O.230.231; 6.O.230.236; 6.O.230.237; 6.O.230.238;6.O.230.239; 6.O.230.154; 6.O.230.157; 6.O.230.166; 6.O.230.169;6.O.230.172; 6.O.230.175; 6.O.230.240; 6.O.230.244; 6.O.231.228;6.O.231.229; 6.O.231.230; 6.O.231.231; 6.O.231.236; 6.O.231.237;6.O.231.238; 6.O.231.239; 6.O.231.154; 6.O.231.157; 6.O.231.166;6.O.231.169; 6.O.231.172; 6.O.231.175; 6.O.231.240; 6.O.231.244;6.O.236.228; 6.O.236.229; 6.O.236.230; 6.O.236.231; 6.O.236.236;6.O.236.237; 6.O.236.238; 6.O.236.239; 6.O.236.154; 6.O.236.157;6.O.236.166; 6.O.236.169; 6.O.236.172; 6.O.236.175; 6.O.236.240;6.O.236.244; 6.O.237.228; 6.O.237.229; 6.O.237.230; 6.O.237.231;6.O.237.236; 6.O.237.237; 6.O.237.238; 6.O.237.239; 6.O.237.154;6.O.237.157; 6.O.237.166; 6.O.237.169; 6.O.237.172; 6.O.237.175;6.O.237.240; 6.O.237.244; 6.O.238.228; 6.O.238.229; 6.O.238.230;6.O.238.231; 6.O.238.236; 6.O.238.237; 6.O.238.238; 6.O.238.239;6.O.238.154; 6.O.238.157; 6.O.238.166; 6.O.238.169; 6.O.238.172;6.O.238.175; 6.O.238.240; 6.O.238.244; 6.O.239.228; 6.O.239.229;6.O.239.230; 6.O.239.231; 6.O.239.236; 6.O.239.237; 6.O.239.238;6.O.239.239; 6.O.239.154; 6.O.239.157; 6.O.239.166; 6.O.239.169;6.O.239.172; 6.O.239.175; 6.O.239.240; 6.O.239.244; 6.O.154.228;6.O.154.229; 6.O.154.230; 6.O.154.231; 6.O.154.236; 6.O.154.237;6.O.154.238; 6.O.154.239; 6.O.154.154; 6.O.154.157; 6.O.154.166;6.O.154.169; 6.O.154.172; 6.O.154.175; 6.O.154.240; 6.O.154.244;6.O.157.228; 6.O.157.229; 6.O.157.230; 6.O.157.231; 6.O.157.236;6.O.157.237; 6.O.157.238; 6.O.157.239; 6.O.157.154; 6.O.157.157;6.O.157.166; 6.O.157.169; 6.O.157.172; 6.O.157.175; 6.O.157.240;6.O.157.244; 6.O.166.228; 6.O.166.229; 6.O.166.230; 6.O.166.231;6.O.166.236; 6.O.166.237; 6.O.166.238; 6.O.166.239; 6.O.166.154;6.O.166.157; 6.O.166.166; 6.O.166.169; 6.O.166.172; 6.O.166.175;6.O.166.240; 6.O.166.244; 6.O.169.228; 6.O.169.229; 6.O.169.230;6.O.169.231; 6.O.169.236; 6.O.169.237; 6.O.169.238; 6.O.169.239;6.O.169.154; 6.O.169.157; 6.O.169.166; 6.O.169.169; 6.O.169.172;6.O.169.175; 6.O.169.240; 6.O.169.244; 6.O.172.228; 6.O.172.229;6.O.172.230; 6.O.172.231; 6.O.172.236; 6.O.172.237; 6.O.172.238;6.O.172.239; 6.O.172.154; 6.O.172.157; 6.O.172.166; 6.O.172.169;6.O.172.172; 6.O.172.175; 6.O.172.240; 6.O.172.244; 6.O.175.228;6.O.175.229; 6.O.175.230; 6.O.175.231; 6.O.175.236; 6.O.175.237;6.O.175.238; 6.O.175.239; 6.O.175.154; 6.O.175.157; 6.O.175.166;6.O.175.169; 6.O.175.172; 6.O.175.175; 6.O.175.240; 6.O.175.244;6.O.240.228; 6.O.240.229; 6.O.240.230; 6.O.240.231; 6.O.240.236;6.O.240.237; 6.O.240.238; 6.O.240.239; 6.O.240.154; 6.O.240.157;6.O.240.166; 6.O.240.169; 6.O.240.172; 6.O.240.175; 6.O.240.240;6.O.240.244; 6.O.244.228; 6.O.244.229; 6.O.244.230; 6.O.244.231;6.O.244.236; 6.O.244.237; 6.O.244.238; 6.O.244.239; 6.O.244.154;6.O.244.157; 6.O.244.166; 6.O.244.169; 6.O.244.172; 6.O.244.175;6.O.244.240; 6.O.244.244; Prodrugs of 6.P 6.P.228.228; 6.P.228.229;6.P.228.230; 6.P.228.231; 6.P.228.236; 6.P.228.237; 6.P.228.238;6.P.228.239; 6.P.228.154; 6.P.228.157; 6.P.228.166; 6.P.228.169;6.P.228.172; 6.P.228.175; 6.P.228.240; 6.P.228.244; 6.P.229.228;6.P.229.229; 6.P.229.230; 6.P.229.231; 6.P.229.236; 6.P.229.237;6.P.229.238; 6.P.229.239; 6.P.229.154; 6.P.229.157; 6.P.229.166;6.P.229.169; 6.P.229.172; 6.P.229.175; 6.P.229.240; 6.P.229.244;6.P.230.228; 6.P.230.229; 6.P.230.230; 6.P.230.231; 6.P.230.236;6.P.230.237; 6.P.230.238; 6.P.230.239; 6.P.230.154; 6.P.230.157;6.P.230.166; 6.P.230.169; 6.P.230.172; 6.P.230.175; 6.P.230.240;6.P.230.244; 6.P.231.228; 6.P.231.229; 6.P.231.230; 6.P.231.231;6.P.231.236; 6.P.231.237; 6.P.231.238; 6.P.231.239; 6.P.231.154;6.P.231.157; 6.P.231.166; 6.P.231.169; 6.P.231.172; 6.P.231.175;6.P.231.240; 6.P.231.244; 6.P.236.228; 6.P.236.229; 6.P.236.230;6.P.236.231; 6.P.236.236; 6.P.236.237; 6.P.236.238; 6.P.236.239;6.P.236.154; 6.P.236.157; 6.P.236.166; 6.P.236.169; 6.P.236.172;6.P.236.175; 6.P.236.240; 6.P.236.244; 6.P.237.228; 6.P.237.229;6.P.237.230; 6.P.237.231; 6.P.237.236; 6.P.237.237; 6.P.237.238;6.P.237.239; 6.P.237.154; 6.P.237.157; 6.P.237.166; 6.P.237.169;6.P.237.172; 6.P.237.175; 6.P.237.240; 6.P.237.244; 6.P.238.228;6.P.238.229; 6.P.238.230; 6.P.238.231; 6.P.238.236; 6.P.238.237;6.P.238.238; 6.P.238.239; 6.P.238.154; 6.P.238.157; 6.P.238.166;6.P.238.169; 6.P.238.172; 6.P.238.175; 6.P.238.240; 6.P.238.244;6.P.239.228; 6.P.239.229; 6.P.239.230; 6.P.239.231; 6.P.239.236;6.P.239.237; 6.P.239.238; 6.P.239.239; 6.P.239.154; 6.P.239.157;6.P.239.166; 6.P.239.169; 6.P.239.172; 6.P.239.175; 6.P.239.240;6.P.239.244; 6.P.154.228; 6.P.154.229; 6.P.154.230; 6.P.154.231;6.P.154.236; 6.P.154.237; 6.P.154.238; 6.P.154.239; 6.P.154.154;6.P.154.157; 6.P.154.166; 6.P.154.169; 6.P.154.172; 6.P.154.175;6.P.154.240; 6.P.154.244; 6.P.157.228; 6.P.157.229; 6.P.157.230;6.P.157.231; 6.P.157.236; 6.P.157.237; 6.P.157.238; 6.P.157.239;6.P.157.154; 6.P.157.157; 6.P.157.166; 6.P.157.169; 6.P.157.172;6.P.157.175; 6.P.157.240; 6.P.157.244; 6.P.166.228; 6.P.166.229;6.P.166.230; 6.P.166.231; 6.P.166.236; 6.P.166.237; 6.P.166.238;6.P.166.239; 6.P.166.154; 6.P.166.157; 6.P.166.166; 6.P.166.169;6.P.166.172; 6.P.166.175; 6.P.166.240; 6.P.166.244; 6.P.169.228;6.P.169.229; 6.P.169.230; 6.P.169.231; 6.P.169.236; 6.P.169.237;6.P.169.238; 6.P.169.239; 6.P.169.154; 6.P.169.157; 6.P.169.166;6.P.169.169; 6.P.169.172; 6.P.169.175; 6.P.169.240; 6.P.169.244;6.P.172.228; 6.P.172.229; 6.P.172.230; 6.P.172.231; 6.P.172.236;6.P.172.237; 6.P.172.238; 6.P.172.239; 6.P.172.154; 6.P.172.157;6.P.172.166; 6.P.172.169; 6.P.172.172; 6.P.172.175; 6.P.172.240;6.P.172.244; 6.P.175.228; 6.P.175.229; 6.P.175.230; 6.P.175.231;6.P.175.236; 6.P.175.237; 6.P.175.238; 6.P.175.239; 6.P.175.154;6.P.175.157; 6.P.175.166; 6.P.175.169; 6.P.175.172; 6.P.175.175;6.P.175.240; 6.P.175.244; 6.P.240.228; 6.P.240.229; 6.P.240.230;6.P.240.231; 6.P.240.236; 6.P.240.237; 6.P.240.238; 6.P.240.239;6.P.240.154; 6.P.240.157; 6.P.240.166; 6.P.240.169; 6.P.240.172;6.P.240.175; 6.P.240.240; 6.P.240.244; 6.P.244.228; 6.P.244.229;6.P.244.230; 6.P.244.231; 6.P.244.236; 6.P.244.237; 6.P.244.238;6.P.244.239; 6.P.244.154; 6.P.244.157; 6.P.244.166; 6.P.244.169;6.P.244.172; 6.P.244.175; 6.P.244.240; 6.P.244.244; Prodrugs of 6.U6.U.228.228; 6.U.228.229; 6.U.228.230; 6.U.228.231; 6.U.228.236;6.U.228.237; 6.U.228.238; 6.U.228.239; 6.U.228.154; 6.U.228.157;6.U.228.166; 6.U.228.169; 6.U.228.172; 6.U.228.175; 6.U.228.240;6.U.228.244; 6.U.229.228; 6.U.229.229; 6.U.229.230; 6.U.229.231;6.U.229.236; 6.U.229.237; 6.U.229.238; 6.U.229.239; 6.U.229.154;6.U.229.157; 6.U.229.166; 6.U.229.169; 6.U.229.172; 6.U.229.175;6.U.229.240; 6.U.229.244; 6.U.230.228; 6.U.230.229; 6.U.230.230;6.U.230.231; 6.U.230.236; 6.U.230.237; 6.U.230.238; 6.U.230.239;6.U.230.154; 6.U.230.157; 6.U.230.166; 6.U.230.169; 6.U.230.172;6.U.230.175; 6.U.230.240; 6.U.230.244; 6.U.231.228; 6.U.231.229;6.U.231.230; 6.U.231.231; 6.U.231.236; 6.U.231.237; 6.U.231.238;6.U.231.239; 6.U.231.154; 6.U.231.157; 6.U.231.166; 6.U.231.169;6.U.231.172; 6.U.231.175; 6.U.231.240; 6.U.231.244; 6.U.236.228;6.U.236.229; 6.U.236.230; 6.U.236.231; 6.U.236.236; 6.U.236.237;6.U.236.238; 6.U.236.239; 6.U.236.154; 6.U.236.157; 6.U.236.166;6.U.236.169; 6.U.236.172; 6.U.236.175; 6.U.236.240; 6.U.236.244;6.U.237.228; 6.U.237.229; 6.U.237.230; 6.U.237.231; 6.U.237.236;6.U.237.237; 6.U.237.238; 6.U.237.239; 6.U.237.154; 6.U.237.157;6.U.237.166; 6.U.237.169; 6.U.237.172; 6.U.237.175; 6.U.237.240;6.U.237.244; 6.U.238.228; 6.U.238.229; 6.U.238.230; 6.U.238.231;6.U.238.236; 6.U.238.237; 6.U.238.238; 6.U.238.239; 6.U.238.154;6.U.238.157; 6.U.238.166; 6.U.238.169; 6.U.238.172; 6.U.238.175;6.U.238.240; 6.U.238.244; 6.U.239.228; 6.U.239.229; 6.U.239.230;6.U.239.231; 6.U.239.236; 6.U.239.237; 6.U.239.238; 6.U.239.239;6.U.239.154; 6.U.239.157; 6.U.239.166; 6.U.239.169; 6.U.239.172;6.U.239.175; 6.U.239.240; 6.U.239.244; 6.U.154.228; 6.U.154.229;6.U.154.230; 6.U.154.231; 6.U.154.236; 6.U.154.237; 6.U.154.238;6.U.154.239; 6.U.154.154; 6.U.154.157; 6.U.154.166; 6.U.154.169;6.U.154.172; 6.U.154.175; 6.U.154.240; 6.U.154.244; 6.U.157.228;6.U.157.229; 6.U.157.230; 6.U.157.231; 6.U.157.236; 6.U.157.237;6.U.157.238; 6.U.157.239; 6.U.157.154; 6.U.157.157; 6.U.157.166;6.U.157.169; 6.U.157.172; 6.U.157.175; 6.U.157.240; 6.U.157.244;6.U.166.228; 6.U.166.229; 6.U.166.230; 6.U.166.231; 6.U.166.236;6.U.166.237; 6.U.166.238; 6.U.166.239; 6.U.166.154; 6.U.166.157;6.U.166.166; 6.U.166.169; 6.U.166.172; 6.U.166.175; 6.U.166.240;6.U.166.244; 6.U.169.228; 6.U.169.229; 6.U.169.230; 6.U.169.231;6.U.169.236; 6.U.169.237; 6.U.169.238; 6.U.169.239; 6.U.169.154;6.U.169.157; 6.U.169.166; 6.U.169.169; 6.U.169.172; 6.U.169.175;6.U.169.240; 6.U.169.244; 6.U.172.228; 6.U.172.229; 6.U.172.230;6.U.172.231; 6.U.172.236; 6.U.172.237; 6.U.172.238; 6.U.172.239;6.U.172.154; 6.U.172.157; 6.U.172.166; 6.U.172.169; 6.U.172.172;6.U.172.175; 6.U.172.240; 6.U.172.244; 6.U.175.228; 6.U.175.229;6.U.175.230; 6.U.175.231; 6.U.175.236; 6.U.175.237; 6.U.175.238;6.U.175.239; 6.U.175.154; 6.U.175.157; 6.U.175.166; 6.U.175.169;6.U.175.172; 6.U.175.175; 6.U.175.240; 6.U.175.244; 6.U.240.228;6.U.240.229; 6.U.240.230; 6.U.240.231; 6.U.240.236; 6.U.240.237;6.U.240.238; 6.U.240.239; 6.U.240.154; 6.U.240.157; 6.U.240.166;6.U.240.169; 6.U.240.172; 6.U.240.175; 6.U.240.240; 6.U.240.244;6.U.244.228; 6.U.244.229; 6.U.244.230; 6.U.244.231; 6.U.244.236;6.U.244.237; 6.U.244.238; 6.U.244.239; 6.U.244.154; 6.U.244.157;6.U.244.166; 6.U.244.169; 6.U.244.172; 6.U.244.175; 6.U.244.240;6.U.244.244; Prodrugs of 6.W 6.W.228.228; 6.W.228.229; 6.W.228.230;6.W.228.231; 6.W.228.236; 6.W.228.237; 6.W.228.238; 6.W.228.239;6.W.228.154; 6.W.228.157; 6.W.228.166; 6.W.228.169; 6.W.228.172;6.W.228.175; 6.W.228.240; 6.W.228.244; 6.W.229.228; 6.W.229.229;6.W.229.230; 6.W.229.231; 6.W.229.236; 6.W.229.237; 6.W.229.238;6.W.229.239; 6.W.229.154; 6.W.229.157; 6.W.229.166; 6.W.229.169;6.W.229.172; 6.W.229.175; 6.W.229.240; 6.W.229.244; 6.W.230.228;6.W.230.229; 6.W.230.230; 6.W.230.231; 6.W.230.236; 6.W.230.237;6.W.230.238; 6.W.230.239; 6.W.230.154; 6.W.230.157; 6.W.230.166;6.W.230.169; 6.W.230.172; 6.W.230.175; 6.W.230.240; 6.W.230.244;6.W.231.228; 6.W.231.229; 6.W.231.230; 6.W.231.231; 6.W.231.236;6.W.231.237; 6.W.231.238; 6.W.231.239; 6.W.231.154; 6.W.231.157;6.W.231.166; 6.W.231.169; 6.W.231.172; 6.W.231.175; 6.W.231.240;6.W.231.244; 6.W.236.228; 6.W.236.229; 6.W.236.230; 6.W.236.231;6.W.236.236; 6.W.236.237; 6.W.236.238; 6.W.236.239; 6.W.236.154;6.W.236.157; 6.W.236.166; 6.W.236.169; 6.W.236.172; 6.W.236.175;6.W.236.240; 6.W.236.244; 6.W.237.228; 6.W.237.229; 6.W.237.230;6.W.237.231; 6.W.237.236; 6.W.237.237; 6.W.237.238; 6.W.237.239;6.W.237.154; 6.W.237.157; 6.W.237.166; 6.W.237.169; 6.W.237.172;6.W.237.175; 6.W.237.240; 6.W.237.244; 6.W.238.228; 6.W.238.229;6.W.238.230; 6.W.238.231; 6.W.238.236; 6.W.238.237; 6.W.238.238;6.W.238.239; 6.W.238.154; 6.W.238.157; 6.W.238.166; 6.W.238.169;6.W.238.172; 6.W.238.175; 6.W.238.240; 6.W.238.244; 6.W.239.228;6.W.239.229; 6.W.239.230; 6.W.239.231; 6.W.239.236; 6.W.239.237;6.W.239.238; 6.W.239.239; 6.W.239.154; 6.W.239.157; 6.W.239.166;6.W.239.169; 6.W.239.172; 6.W.239.175; 6.W.239.240; 6.W.239.244;6.W.154.228; 6.W.154.229; 6.W.154.230; 6.W.154.231; 6.W.154.236;6.W.154.237; 6.W.154.238; 6.W.154.239; 6.W.154.154; 6.W.154.157;6.W.154.166; 6.W.154.169; 6.W.154.172; 6.W.154.175; 6.W.154.240;6.W.154.244; 6.W.157.228; 6.W.157.229; 6.W.157.230; 6.W.157.231;6.W.157.236; 6.W.157.237; 6.W.157.238; 6.W.157.239; 6.W.157.154;6.W.157.157; 6.W.157.166; 6.W.157.169; 6.W.157.172; 6.W.157.175;6.W.157.240; 6.W.157.244; 6.W.166.228; 6.W.166.229; 6.W.166.230;6.W.166.231; 6.W.166.236; 6.W.166.237; 6.W.166.238; 6.W.166.239;6.W.166.154; 6.W.166.157; 6.W.166.166; 6.W.166.169; 6.W.166.172;6.W.166.175; 6.W.166.240; 6.W.166.244; 6.W.169.228; 6.W.169.229;6.W.169.230; 6.W.169.231; 6.W.169.236; 6.W.169.237; 6.W.169.238;6.W.169.239; 6.W.169.154; 6.W.169.157; 6.W.169.166; 6.W.169.169;6.W.169.172; 6.W.169.175; 6.W.169.240; 6.W.169.244; 6.W.172.228;6.W.172.229; 6.W.172.230; 6.W.172.231; 6.W.172.236; 6.W.172.237;6.W.172.238; 6.W.172.239; 6.W.172.154; 6.W.172.157; 6.W.172.166;6.W.172.169; 6.W.172.172; 6.W.172.175; 6.W.172.240; 6.W.172.244;6.W.175.228; 6.W.175.229; 6.W.175.230; 6.W.175.231; 6.W.175.236;6.W.175.237; 6.W.175.238; 6.W.175.239; 6.W.175.154; 6.W.175.157;6.W.175.166; 6.W.175.169; 6.W.175.172; 6.W.175.175; 6.W.175.240;6.W.175.244; 6.W.240.228; 6.W.240.229; 6.W.240.230; 6.W.240.231;6.W.240.236; 6.W.240.237; 6.W.240.238; 6.W.240.239; 6.W.240.154;6.W.240.157; 6.W.240.166; 6.W.240.169; 6.W.240.172; 6.W.240.175;6.W.240.240; 6.W.240.244; 6.W.244.228; 6.W.244.229; 6.W.244.230;6.W.244.231; 6.W.244.236; 6.W.244.237; 6.W.244.238; 6.W.244.239;6.W.244.154; 6.W.244.157; 6.W.244.166; 6.W.244.169; 6.W.244.172;6.W.244.175; 6.W.244.240; 6.W.244.244; Prodrugs of 6.Y 6.Y.228.228;6.Y.228.229; 6.Y.228.230; 6.Y.228.231; 6.Y.228.236; 6.Y.228.237;6.Y.228.238; 6.Y.228.239; 6.Y.228.154; 6.Y.228.157; 6.Y.228.166;6.Y.228.169; 6.Y.228.172; 6.Y.228.175; 6.Y.228.240; 6.Y.228.244;6.Y.229.228; 6.Y.229.229; 6.Y.229.230; 6.Y.229.231; 6.Y.229.236;6.Y.229.237; 6.Y.229.238; 6.Y.229.239; 6.Y.229.154; 6.Y.229.157;6.Y.229.166; 6.Y.229.169; 6.Y.229.172; 6.Y.229.175; 6.Y.229.240;6.Y.229.244; 6.Y.230.228; 6.Y.230.229; 6.Y.230.230; 6.Y.230.231;6.Y.230.236; 6.Y.230.237; 6.Y.230.238; 6.Y.230.239; 6.Y.230.154;6.Y.230.157; 6.Y.230.166; 6.Y.230.169; 6.Y.230.172; 6.Y.230.175;6.Y.230.240; 6.Y.230.244; 6.Y.231.228; 6.Y.231.229; 6.Y.231.230;6.Y.231.231; 6.Y.231.236; 6.Y.231.237; 6.Y.231.238; 6.Y.231.239;6.Y.231.154; 6.Y.231.157; 6.Y.231.166; 6.Y.231.169; 6.Y.231.172;6.Y.231.175; 6.Y.231.240; 6.Y.231.244; 6.Y.236.228; 6.Y.236.229;6.Y.236.230; 6.Y.236.231; 6.Y.236.236; 6.Y.236.237; 6.Y.236.238;6.Y.236.239; 6.Y.236.154; 6.Y.236.157; 6.Y.236.166; 6.Y.236.169;6.Y.236.172; 6.Y.236.175; 6.Y.236.240; 6.Y.236.244; 6.Y.237.228;6.Y.237.229; 6.Y.237.230; 6.Y.237.231; 6.Y.237.236; 6.Y.237.237;6.Y.237.238; 6.Y.237.239; 6.Y.237.154; 6.Y.237.157; 6.Y.237.166;6.Y.237.169; 6.Y.237.172; 6.Y.237.175; 6.Y.237.240; 6.Y.237.244;6.Y.238.228; 6.Y.238.229; 6.Y.238.230; 6.Y.238.231; 6.Y.238.236;6.Y.238.237; 6.Y.238.238; 6.Y.238.239; 6.Y.238.154; 6.Y.238.157;6.Y.238.166; 6.Y.238.169; 6.Y.238.172; 6.Y.238.175; 6.Y.238.240;6.Y.238.244; 6.Y.239.228; 6.Y.239.229; 6.Y.239.230; 6.Y.239.231;6.Y.239.236; 6.Y.239.237; 6.Y.239.238; 6.Y.239.239; 6.Y.239.154;6.Y.239.157; 6.Y.239.166; 6.Y.239.169; 6.Y.239.172; 6.Y.239.175;6.Y.239.240; 6.Y.239.244; 6.Y.154.228; 6.Y.154.229; 6.Y.154.230;6.Y.154.231; 6.Y.154.236; 6.Y.154.237; 6.Y.154.238; 6.Y.154.239;6.Y.154.154; 6.Y.154.157; 6.Y.154.166; 6.Y.154.169; 6.Y.154.172;6.Y.154.175; 6.Y.154.240; 6.Y.154.244; 6.Y.157.228; 6.Y.157.229;6.Y.157.230; 6.Y.157.231; 6.Y.157.236; 6.Y.157.237; 6.Y.157.238;6.Y.157.239; 6.Y.157.154; 6.Y.157.157; 6.Y.157.166; 6.Y.157.169;6.Y.157.172; 6.Y.157.175; 6.Y.157.240; 6.Y.157.244; 6.Y.166.228;6.Y.166.229; 6.Y.166.230; 6.Y.166.231; 6.Y.166.236; 6.Y.166.237;6.Y.166.238; 6.Y.166.239; 6.Y.166.154; 6.Y.166.157; 6.Y.166.166;6.Y.166.169; 6.Y.166.172; 6.Y.166.175; 6.Y.166.240; 6.Y.166.244;6.Y.169.228; 6.Y.169.229; 6.Y.169.230; 6.Y.169.231; 6.Y.169.236;6.Y.169.237; 6.Y.169.238; 6.Y.169.239; 6.Y.169.154; 6.Y.169.157;6.Y.169.166; 6.Y.169.169; 6.Y.169.172; 6.Y.169.175; 6.Y.169.240;6.Y.169.244; 6.Y.172.228; 6.Y.172.229; 6.Y.172.230; 6.Y.172.231;6.Y.172.236; 6.Y.172.237; 6.Y.172.238; 6.Y.172.239; 6.Y.172.154;6.Y.172.157; 6.Y.172.166; 6.Y.172.169; 6.Y.172.172; 6.Y.172.175;6.Y.172.240; 6.Y.172.244; 6.Y.175.228; 6.Y.175.229; 6.Y.175.230;6.Y.175.231; 6.Y.175.236; 6.Y.175.237; 6.Y.175.238; 6.Y.175.239;6.Y.175.154; 6.Y.175.157; 6.Y.175.166; 6.Y.175.169; 6.Y.175.172;6.Y.175.175; 6.Y.175.240; 6.Y.175.244; 6.Y.240.228; 6.Y.240.229;6.Y.240.230; 6.Y.240.231; 6.Y.240.236; 6.Y.240.237; 6.Y.240.238;6.Y.240.239; 6.Y.240.154; 6.Y.240.157; 6.Y.240.166; 6.Y.240.169;6.Y.240.172; 6.Y.240.175; 6.Y.240.240; 6.Y.240.244; 6.Y.244.228;6.Y.244.229; 6.Y.244.230; 6.Y.244.231; 6.Y.244.236; 6.Y.244.237;6.Y.244.238; 6.Y.244.239; 6.Y.244.154; 6.Y.244.157; 6.Y.244.166;6.Y.244.169; 6.Y.244.172; 6.Y.244.175; 6.Y.244.240; 6.Y.244.244;Prodrugs of 7.AH 7.AH.4.157; 7.AH.4.158; 7.AH.4.196; 7.AH.4.223;7.AH.4.240; 7.AH.4.244; 7.AH.4.243; 7.AH.4.247; 7.AH.5.157; 7.AH.5.158;7.AH.5.196; 7.AH.5.223; 7.AH.5.240; 7.AH.5.244; 7.AH.5.243; 7.AH.5.247;7.AH.7.157; 7.AH.7.158; 7.AH.7.196; 7.AH.7.223; 7.AH.7.240; 7.AH.7.244;7.AH.7.243; 7.AH.7.247; 7.AH.15.157; 7.AH.15.158; 7.AH.15.196;7.AH.15.223; 7.AH.15.240; 7.AH.15.244; 7.AH.15.243; 7.AH.15.247;7.AH.16.157; 7.AH.16.158; 7.AH.16.196; 7.AH.16.223; 7.AH.16.240;7.AH.16.244; 7.AH.16.243; 7.AH.16.247; 7.AH.18.157; 7.AH.18.158;7.AH.18.196; 7.AH.18.223; 7.AH.18.240; 7.AH.18.244; 7.AH.18.243;7.AH.18.247; 7.AH.26.157; 7.AH.26.158; 7.AH.26.196; 7.AH.26.223;7.AH.26.240; 7.AH.26.244; 7.AH.26.243; 7.AH.26.247; 7.AH.27.157;7.AH.27.158; 7.AH.27.196; 7.AH.27.223; 7.AH.27.240; 7.AH.27.244;7.AH.27.243; 7.AH.27.247; 7.AH.29.157; 7.AH.29.158; 7.AH.29.196;7.AH.29.223; 7.AH.29.240; 7.AH.29.244; 7.AH.29.243; 7.AH.29.247;7.AH.54.157; 7.AH.54.158; 7.AH.54.196; 7.AH.54.223; 7.AH.54.240;7.AH.54.244; 7.AH.54.243; 7.AH.54.247; 7.AH.55.157; 7.AH.55.158;7.AH.55.196; 7.AH.55.223; 7.AH.55.240; 7.AH.55.244; 7.AH.55.243;7.AH.55.247; 7.AH.56.157; 7.AH.56.158; 7.AH.56.196; 7.AH.56.223;7.AH.56.240; 7.AH.56.244; 7.AH.56.243; 7.AH.56.247; 7.AH.157.157;7.AH.157.158; 7.AH.157.196; 7.AH.157.223; 7.AH.157.240; 7.AH.157.244;7.AH.157.243; 7.AH.157.247; 7.AH.196.157; 7.AH.196.158; 7.AH.196.196;7.AH.196.223; 7.AH.196.240; 7.AH.196.244; 7.AH.196.243; 7.AH.196.247;7.AH.223.157; 7.AH.223.158; 7.AH.223.196; 7.AH.223.223; 7.AH.223.240;7.AH.223.244; 7.AH.223.243; 7.AH.223.247; 7.AH.240.157; 7.AH.240.158;7.AH.240.196; 7.AH.240.223; 7.AH.240.240; 7.AH.240.244; 7.AH.240.243;7.AH.240.247; 7.AH.244.157; 7.AH.244.158; 7.AH.244.196; 7.AH.244.223;7.AH.244.240; 7.AH.244.244; 7.AH.244.243; 7.AH.244.247; 7.AH.247.157;7.AH.247.158; 7.AH.247.196; 7.AH.247.223; 7.AH.247.240; 7.AH.247.244;7.AH.247.243; 7.AH.247.247; Prodrugs of 7.AJ 7.AJ.4.157; 7.AJ.4.158;7.AJ.4.196; 7.AJ.4.223; 7.AJ.4.240; 7.AJ.4.244; 7.AJ.4.243; 7.AJ.4.247;7.AJ.5.157; 7.AJ.5.158; 7.AJ.5.196; 7.AJ.5.223; 7.AJ.5.240; 7.AJ.5.244;7.AJ.5.243; 7.AJ.5.247; 7.AJ.7.157; 7.AJ.7.158; 7.AJ.7.196; 7.AJ.7.223;7.AJ.7.240; 7.AJ.7.244; 7.AJ.7.243; 7.AJ.7.247; 7.AJ.15.157;7.AJ.15.158; 7.AJ.15.196; 7.AJ.15.223; 7.AJ.15.240; 7.AJ.15.244;7.AJ.15.243; 7.AJ.15.247; 7.AJ.16.157; 7.AJ.16.158; 7.AJ.16.196;7.AJ.16.223; 7.AJ.16.240; 7.AJ.16.244; 7.AJ.16.243; 7.AJ.16.247;7.AJ.18.157; 7.AJ.18.158; 7.AJ.18.196; 7.AJ.18.223; 7.AJ.18.240;7.AJ.18.244; 7.AJ.18.243; 7.AJ.18.247; 7.AJ.26.157; 7.AJ.26.158;7.AJ.26.196; 7.AJ.26.223; 7.AJ.26.240; 7.AJ.26.244; 7.AJ.26.243;7.AJ.26.247; 7.AJ.27.157; 7.AJ.27.158; 7.AJ.27.196; 7.AJ.27.223;7.AJ.27.240; 7.AJ.27.244; 7.AJ.27.243; 7.AJ.27.247; 7.AJ.29.157;7.AJ.29.158; 7.AJ.29.196; 7.AJ.29.223; 7.AJ.29.240; 7.AJ.29.244;7.AJ.29.243; 7.AJ.29.247; 7.AJ.54.157; 7.AJ.54.158; 7.AJ.54.196;7.AJ.54.223; 7.AJ.54.240; 7.AJ.54.244; 7.AJ.54.243; 7.AJ.54.247;7.AJ.55.157; 7.AJ.55.158; 7.AJ.55.196; 7.AJ.55.223; 7.AJ.55.240;7.AJ.55.244; 7.AJ.55.243; 7.AJ.55.247; 7.AJ.56.157; 7.AJ.56.158;7.AJ.56.196; 7.AJ.56.223; 7.AJ.56.240; 7.AJ.56.244; 7.AJ.56.243;7.AJ.56.247; 7.AJ.157.157; 7.AJ.157.158; 7.AJ.157.196; 7.AJ.157.223;7.AJ.157.240; 7.AJ.157.244; 7.AJ.157.243; 7.AJ.157.247; 7.AJ.196.157;7.AJ.196.158; 7.AJ.196.196; 7.AJ.196.223; 7.AJ.196.240; 7.AJ.196.244;7.AJ.196.243; 7.AJ.196.247; 7.AJ.223.157; 7.AJ.223.158; 7.AJ.223.196;7.AJ.223.223; 7.AJ.223.240; 7.AJ.223.244; 7.AJ.223.243; 7.AJ.223.247;7.AJ.240.157; 7.AJ.240.158; 7.AJ.240.196; 7.AJ.240.223; 7.AJ.240.240;7.AJ.240.244; 7.AJ.240.243; 7.AJ.240.247; 7.AJ.244.157; 7.AJ.244.158;7.AJ.244.196; 7.AJ.244.223; 7.AJ.244.240; 7.AJ.244.244; 7.AJ.244.243;7.AJ.244.247; 7.AJ.247.157; 7.AJ.247.158; 7.AJ.247.196; 7.AJ.247.223;7.AJ.247.240; 7.AJ.247.244; 7.AJ.247.243; 7.AJ.247.247; Prodrugs of 7.AN7.AN.4.157; 7.AN.4.158; 7.AN.4.196; 7.AN.4.223; 7.AN.4.240; 7.AN.4.244;7.AN.4.243; 7.AN.4.247; 7.AN.5.157; 7.AN.5.158; 7.AN.5.196; 7.AN.5.223;7.AN.5.240; 7.AN.5.244; 7.AN.5.243; 7.AN.5.247; 7.AN.7.157; 7.AN.7.158;7.AN.7.196; 7.AN.7.223; 7.AN.7.240; 7.AN.7.244; 7.AN.7.243; 7.AN.7.247;7.AN.15.157; 7.AN.15.158; 7.AN.15.196; 7.AN.15.223; 7.AN.15.240;7.AN.15.244; 7.AN.15.243; 7.AN.15.247; 7.AN.16.157; 7.AN.16.158;7.AN.16.196; 7.AN.16.223; 7.AN.16.240; 7.AN.16.244; 7.AN.16.243;7.AN.16.247; 7.AN.18.157; 7.AN.18.158; 7.AN.18.196; 7.AN.18.223;7.AN.18.240; 7.AN.18.244; 7.AN.18.243; 7.AN.18.247; 7.AN.26.157;7.AN.26.158; 7.AN.26.196; 7.AN.26.223; 7.AN.26.240; 7.AN.26.244;7.AN.26.243; 7.AN.26.247; 7.AN.27.157; 7.AN.27.158; 7.AN.27.196;7.AN.27.223; 7.AN.27.240; 7.AN.27.244; 7.AN.27.243; 7.AN.27.247;7.AN.29.157; 7.AN.29.158; 7.AN.29.196; 7.AN.29.223; 7.AN.29.240;7.AN.29.244; 7.AN.29.243; 7.AN.29.247; 7.AN.54.157; 7.AN.54.158;7.AN.54.196; 7.AN.54.223; 7.AN.54.240; 7.AN.54.244; 7.AN.54.243;7.AN.54.247; 7.AN.55.157; 7.AN.55.158; 7.AN.55.196; 7.AN.55.223;7.AN.55.240; 7.AN.55.244; 7.AN.55.243; 7.AN.55.247; 7.AN.56.157;7.AN.56.158; 7.AN.56.196; 7.AN.56.223; 7.AN.56.240; 7.AN.56.244;7.AN.56.243; 7.AN.56.247; 7.AN.157.157; 7.AN.157.158; 7.AN.157.196;7.AN.157.223; 7.AN.157.240; 7.AN.157.244; 7.AN.157.243; 7.AN.157.247;7.AN.196.157; 7.AN.196.158; 7.AN.196.196; 7.AN.196.223; 7.AN.196.240;7.AN.196.244; 7.AN.196.243; 7.AN.196.247; 7.AN.223.157; 7.AN.223.158;7.AN.223.196; 7.AN.223.223; 7.AN.223.240; 7.AN.223.244; 7.AN.223.243;7.AN.223.247; 7.AN.240.157; 7.AN.240.158; 7.AN.240.196; 7.AN.240.223;7.AN.240.240; 7.AN.240.244; 7.AN.240.243; 7.AN.240.247; 7.AN.244.157;7.AN.244.158; 7.AN.244.196; 7.AN.244.223; 7.AN.244.240; 7.AN.244.244;7.AN.244.243; 7.AN.244.247; 7.AN.247.157; 7.AN.247.158; 7.AN.247.196;7.AN.247.223; 7.AN.247.240; 7.AN.247.244; 7.AN.247.243; 7.AN.247.247;Prodrugs of 7.AP 7.AP.4.157; 7.AP.4.158; 7.AP.4.196; 7.AP.4.223;7.AP.4.240; 7.AP.4.244; 7.AP.4.243; 7.AP.4.247; 7.AP.5.157; 7.AP.5.158;7.AP.5.196; 7.AP.5.223; 7.AP.5.240; 7.AP.5.244; 7.AP.5.243; 7.AP.5.247;7.AP.7.157; 7.AP.7.158; 7.AP.7.196; 7.AP.7.223; 7.AP.7.240; 7.AP.7.244;7.AP.7.243; 7.AP.7.247; 7.AP.15.157; 7.AP.15.158; 7.AP.15.196;7.AP.15.223; 7.AP.15.240; 7.AP.15.244; 7.AP.15.243; 7.AP.15.247;7.AP.16.157; 7.AP.16.158; 7.AP.16.196; 7.AP.16.223; 7.AP.16.240;7.AP.16.244; 7.AP.16.243; 7.AP.16.247; 7.AP.18.157; 7.AP.18.158;7.AP.18.196; 7.AP.18.223; 7.AP.18.240; 7.AP.18.244; 7.AP.18.243;7.AP.18.247; 7.AP.26.157; 7.AP.26.158; 7.AP.26.196; 7.AP.26.223;7.AP.26.240; 7.AP.26.244; 7.AP.26.243; 7.AP.26.247; 7.AP.27.157;7.AP.27.158; 7.AP.27.196; 7.AP.27.223; 7.AP.27.240; 7.AP.27.244;7.AP.27.243; 7.AP.27.247; 7.AP.29.157; 7.AP.29.158; 7.AP.29.196;7.AP.29.223; 7.AP.29.240; 7.AP.29.244; 7.AP.29.243; 7.AP.29.247;7.AP.54.157; 7.AP.54.158; 7.AP.54.196; 7.AP.54.223; 7.AP.54.240;7.AP.54.244; 7.AP.54.243; 7.AP.54.247; 7.AP.55.157; 7.AP.55.158;7.AP.55.196; 7.AP.55.223; 7.AP.55.240; 7.AP.55.244; 7.AP.55.243;7.AP.55.247; 7.AP.56.157; 7.AP.56.158; 7.AP.56.196; 7.AP.56.223;7.AP.56.240; 7.AP.56.244; 7.AP.56.243; 7.AP.56.247; 7.AP.157.157;7.AP.157.158; 7.AP.157.196; 7.AP.157.223; 7.AP.157.240; 7.AP.157.244;7.AP.157.243; 7.AP.157.247; 7.AP.196.157; 7.AP.196.158; 7.AP.196.196;7.AP.196.223; 7.AP.196.240; 7.AP.196.244; 7.AP.196.243; 7.AP.196.247;7.AP.223.157; 7.AP.223.158; 7.AP.223.196; 7.AP.223.223; 7.AP.223.240;7.AP.223.244; 7.AP.223.243; 7.AP.223.247; 7.AP.240.157; 7.AP.240.158;7.AP.240.196; 7.AP.240.223; 7.AP.240.240; 7.AP.240.244; 7.AP.240.243;7.AP.240.247; 7.AP.244.157; 7.AP.244.158; 7.AP.244.196; 7.AP.244.223;7.AP.244.240; 7.AP.244.244; 7.AP.244.243; 7.AP.244.247; 7.AP.247.157;7.AP.247.158; 7.AP.247.196; 7.AP.247.223; 7.AP.247.240; 7.AP.247.244;7.AP.247.243; 7.AP.247.247; Prodrugs of 7.AZ 7.AZ.4.157; 7.AZ.4.158;7.AZ.4.196; 7.AZ.4.223; 7.AZ.4.240; 7.AZ.4.244; 7.AZ.4.243; 7.AZ.4.247;7.AZ.5.157; 7.AZ.5.158; 7.AZ.5.196; 7.AZ.5.223; 7.AZ.5.240; 7.AZ.5.244;7.AZ.5.243; 7.AZ.5.247; 7.AZ.7.157; 7.AZ.7.158; 7.AZ.7.196; 7.AZ.7.223;7.AZ.7.240; 7.AZ.7.244; 7.AZ.7.243; 7.AZ.7.247; 7.AZ.15.157;7.AZ.15.158; 7.AZ.15.196; 7.AZ.15.223; 7.AZ.15.240; 7.AZ.15.244;7.AZ.15.243; 7.AZ.15.247; 7.AZ.16.157; 7.AZ.16.158; 7.AZ.16.196;7.AZ.16.223; 7.AZ.16.240; 7.AZ.16.244; 7.AZ.16.243; 7.AZ.16.247;7.AZ.18.157; 7.AZ.18.158; 7.AZ.18.196; 7.AZ.18.223; 7.AZ.18.240;7.AZ.18.244; 7.AZ.18.243; 7.AZ.18.247; 7.AZ.26.157; 7.AZ.26.158;7.AZ.26.196; 7.AZ.26.223; 7.AZ.26.240; 7.AZ.26.244; 7.AZ.26.243;7.AZ.26.247; 7.AZ.27.157; 7.AZ.27.158; 7.AZ.27.196; 7.AZ.27.223;7.AZ.27.240; 7.AZ.27.244; 7.AZ.27.243; 7.AZ.27.247; 7.AZ.29.157;7.AZ.29.158; 7.AZ.29.196; 7.AZ.29.223; 7.AZ.29.240; 7.AZ.29.244;7.AZ.29.243; 7.AZ.29.247; 7.AZ.54.157; 7.AZ.54.158; 7.AZ.54.196;7.AZ.54.223; 7.AZ.54.240; 7.AZ.54.244; 7.AZ.54.243; 7.AZ.54.247;7.AZ.55.157; 7.AZ.55.158; 7.AZ.55.196; 7.AZ.55.223; 7.AZ.55.240;7.AZ.55.244; 7.AZ.55.243; 7.AZ.55.247; 7.AZ.56.157; 7.AZ.56.158;7.AZ.56.196; 7.AZ.56.223; 7.AZ.56.240; 7.AZ.56.244; 7.AZ.56.243;7.AZ.56.247; 7.AZ.157.157; 7.AZ.157.158; 7.AZ.157.196; 7.AZ.157.223;7.AZ.157.240; 7.AZ.157.244; 7.AZ.157.243; 7.AZ.157.247; 7.AZ.196.157;7.AZ.196.158; 7.AZ.196.196; 7.AZ.196.223; 7.AZ.196.240; 7.AZ.196.244;7.AZ.196.243; 7.AZ.196.247; 7.AZ.223.157; 7.AZ.223.158; 7.AZ.223.196;7.AZ.223.223; 7.AZ.223.240; 7.AZ.223.244; 7.AZ.223.243; 7.AZ.223.247;7.AZ.240.157; 7.AZ.240.158; 7.AZ.240.196; 7.AZ.240.223; 7.AZ.240.240;7.AZ.240.244; 7.AZ.240.243; 7.AZ.240.247; 7.AZ.244.157; 7.AZ.244.158;7.AZ.244.196; 7.AZ.244.223; 7.AZ.244.240; 7.AZ.244.244; 7.AZ.244.243;7.AZ.244.247; 7.AZ.247.157; 7.AZ.247.158; 7.AZ.247.196; 7.AZ.247.223;7.AZ.247.240; 7.AZ.247.244; 7.AZ.247.243; 7.AZ.247.247; Prodrugs of 7.BF7.BF.4.157; 7.BF.4.158; 7.BF.4.196; 7.BF.4.223; 7.BF.4.240; 7.BF.4.244;7.BF.4.243; 7.BF.4.247; 7.BF.5.157; 7.BF.5.158; 7.BF.5.196; 7.BF.5.223;7.BF.5.240; 7.BF.5.244; 7.BF.5.243; 7.BF.5.247; 7.BF.7.157; 7.BF.7.158;7.BF.7.196; 7.BF.7.223; 7.BF.7.240; 7.BF.7.244; 7.BF.7.243; 7.BF.7.247;7.BF.15.157; 7.BF.15.158; 7.BF.15.196; 7.BF.15.223; 7.BF.15.240;7.BF.15.244; 7.BF.15.243; 7.BF.15.247; 7.BF.16.157; 7.BF.16.158;7.BF.16.196; 7.BF.16.223; 7.BF.16.240; 7.BF.16.244; 7.BF.16.243;7.BF.16.247; 7.BF.18.157; 7.BF.18.158; 7.BF.18.196; 7.BF.18.223;7.BF.18.240; 7.BF.18.244; 7.BF.18.243; 7.BF.18.247; 7.BF.26.157;7.BF.26.158; 7.BF.26.196; 7.BF.26.223; 7.BF.26.240; 7.BF.26.244;7.BF.26.243; 7.BF.26.247; 7.BF.27.157; 7.BF.27.158; 7.BF.27.196;7.BF.27.223; 7.BF.27.240; 7.BF.27.244; 7.BF.27.243; 7.BF.27.247;7.BF.29.157; 7.BF.29.158; 7.BF.29.196; 7.BF.29.223; 7.BF.29.240;7.BF.29.244; 7.BF.29.243; 7.BF.29.247; 7.BF.54.157; 7.BF.54.158;7.BF.54.196; 7.BF.54.223; 7.BF.54.240; 7.BF.54.244; 7.BF.54.243;7.BF.54.247; 7.BF.55.157; 7.BF.55.158; 7.BF.55.196; 7.BF.55.223;7.BF.55.240; 7.BF.55.244; 7.BF.55.243; 7.BF.55.247; 7.BF.56.157;7.BF.56.158; 7.BF.56.196; 7.BF.56.223; 7.BF.56.240; 7.BF.56.244;7.BF.56.243; 7.BF.56.247; 7.BF.157.157; 7.BF.157.158; 7.BF.157.196;7.BF.157.223; 7.BF.157.240; 7.BF.157.244; 7.BF.157.243; 7.BF.157.247;7.BF.196.157; 7.BF.196.158; 7.BF.196.196; 7.BF.196.223; 7.BF.196.240;7.BF.196.244; 7.BF.196.243; 7.BF.196.247; 7.BF.223.157; 7.BF.223.158;7.BF.223.196; 7.BF.223.223; 7.BF.223.240; 7.BF.223.244; 7.BF.223.243;7.BF.223.247; 7.BF.240.157; 7.BF.240.158; 7.BF.240.196; 7.BF.240.223;7.BF.240.240; 7.BF.240.244; 7.BF.240.243; 7.BF.240.247; 7.BF.244.157;7.BF.244.158; 7.BF.244.196; 7.BF.244.223; 7.BF.244.240; 7.BF.244.244;7.BF.244.243; 7.BF.244.247; 7.BF.247.157; 7.BF.247.158; 7.BF.247.196;7.BF.247.223; 7.BF.247.240; 7.BF.247.244; 7.BF.247.243; 7.BF.247.247;Prodrugs of 7.CI 7.CI.4.157; 7.CI.4.158; 7.CI.4.196; 7.CI.4.223;7.CI.4.240; 7.CI.4.244; 7.CI.4.243; 7.CI.4.247; 7.CI.5.157; 7.CI.5.158;7.CI.5.196; 7.CI.5.223; 7.CI.5.240; 7.CI.5.244; 7.CI.5.243; 7.CI.5.247;7.CI.7.157; 7.CI.7.158; 7.CI.7.196; 7.CI.7.223; 7.CI.7.240; 7.CI.7.244;7.CI.7.243; 7.CI.7.247; 7.CI.15.157; 7.CI.15.158; 7.CI.15.196;7.CI.15.223; 7.CI.15.240; 7.CI.15.244; 7.CI.15.243; 7.CI.15.247;7.CI.16.157; 7.CI.16.158; 7.CI.16.196; 7.CI.16.223; 7.CI.16.240;7.CI.16.244; 7.CI.16.243; 7.CI.16.247; 7.CI.18.157; 7.CI.18.158;7.CI.18.196; 7.CI.18.223; 7.CI.18.240; 7.CI.18.244; 7.CI.18.243;7.CI.18.247; 7.CI.26.157; 7.CI.26.158; 7.CI.26.196; 7.CI.26.223;7.CI.26.240; 7.CI.26.244; 7.CI.26.243; 7.CI.26.247; 7.CI.27.157;7.CI.27.158; 7.CI.27.196; 7.CI.27.223; 7.CI.27.240; 7.CI.27.244;7.CI.27.243; 7.CI.27.247; 7.CI.29.157; 7.CI.29.158; 7.CI.29.196;7.CI.29.223; 7.CI.29.240; 7.CI.29.244; 7.CI.29.243; 7.CI.29.247;7.CI.54.157; 7.CI.54.158; 7.CI.54.196; 7.CI.54.223; 7.CI.54.240;7.CI.54.244; 7.CI.54.243; 7.CI.54.247; 7.CI.55.157; 7.CI.55.158;7.CI.55.196; 7.CI.55.223; 7.CI.55.240; 7.CI.55.244; 7.CI.55.243;7.CI.55.247; 7.CI.56.157; 7.CI.56.158; 7.CI.56.196; 7.CI.56.223;7.CI.56.240; 7.CI.56.244; 7.CI.56.243; 7.CI.56.247; 7.CI.157.157;7.CI.157.158; 7.CI.157.196; 7.CI.157.223; 7.CI.157.240; 7.CI.157.244;7.CI.157.243; 7.CI.157.247; 7.CI.196.157; 7.CI.196.158; 7.CI.196.196;7.CI.196.223; 7.CI.196.240; 7.CI.196.244; 7.CI.196.243; 7.CI.196.247;7.CI.223.157; 7.CI.223.158; 7.CI.223.196; 7.CI.223.223; 7.CI.223.240;7.CI.223.244; 7.CI.223.243; 7.CI.223.247; 7.CI.240.157; 7.CI.240.158;7.CI.240.196; 7.CI.240.223; 7.CI.240.240; 7.CI.240.244; 7.CI.240.243;7.CI.240.247; 7.CI.244.157; 7.CI.244.158; 7.CI.244.196; 7.CI.244.223;7.CI.244.240; 7.CI.244.244; 7.CI.244.243; 7.CI.244.247; 7.CI.247.157;7.CI.247.158; 7.CI.247.196; 7.CI.247.223; 7.CI.247.240; 7.CI.247.244;7.CI.247.243; 7.CI.247.247; Prodrugs of 7.CO 7.CO.4.157; 7.CO.4.158;7.CO.4.196; 7.CO.4.223; 7.CO.4.240; 7.CO.4.244; 7.CO.4.243; 7.CO.4.247;7.CO.5.157; 7.CO.5.158; 7.CO.5.196; 7.CO.5.223; 7.CO.5.240; 7.CO.5.244;7.CO.5.243; 7.CO.5.247; 7.CO.7.157; 7.CO.7.158; 7.CO.7.196; 7.CO.7.223;7.CO.7.240; 7.CO.7.244; 7.CO.7.243; 7.CO.7.247; 7.CO.15.157;7.CO.15.158; 7.CO.15.196; 7.CO.15.223; 7.CO.15.240; 7.CO.15.244;7.CO.15.243; 7.CO.15.247; 7.CO.16.157; 7.CO.16.158; 7.CO.16.196;7.CO.16.223; 7.CO.16.240; 7.CO.16.244; 7.CO.16.243; 7.CO.16.247;7.CO.18.157; 7.CO.18.158; 7.CO.18.196; 7.CO.18.223; 7.CO.18.240;7.CO.18.244; 7.CO.18.243; 7.CO.18.247; 7.CO.26.157; 7.CO.26.158;7.CO.26.196; 7.CO.26.223; 7.CO.26.240; 7.CO.26.244; 7.CO.26.243;7.CO.26.247; 7.CO.27.157; 7.CO.27.158; 7.CO.27.196; 7.CO.27.223;7.CO.27.240; 7.CO.27.244; 7.CO.27.243; 7.CO.27.247; 7.CO.29.157;7.CO.29.158; 7.CO.29.196; 7.CO.29.223; 7.CO.29.240; 7.CO.29.244;7.CO.29.243; 7.CO.29.247; 7.CO.54.157; 7.CO.54.158; 7.CO.54.196;7.CO.54.223; 7.CO.54.240; 7.CO.54.244; 7.CO.54.243; 7.CO.54.247;7.CO.55.157; 7.CO.55.158; 7.CO.55.196; 7.CO.55.223; 7.CO.55.240;7.CO.55.244; 7.CO.55.243; 7.CO.55.247; 7.CO.56.157; 7.CO.56.158;7.CO.56.196; 7.CO.56.223; 7.CO.56.240; 7.CO.56.244; 7.CO.56.243;7.CO.56.247; 7.CO.157.157; 7.CO.157.158; 7.CO.157.196; 7.CO.157.223;7.CO.157.240; 7.CO.157.244; 7.CO.157.243; 7.CO.157.247; 7.CO.196.157;7.CO.196.158; 7.CO.196.196; 7.CO.196.223; 7.CO.196.240; 7.CO.196.244;7.CO.196.243; 7.CO.196.247; 7.CO.223.157; 7.CO.223.158; 7.CO.223.196;7.CO.223.223; 7.CO.223.240; 7.CO.223.244; 7.CO.223.243; 7.CO.223.247;7.CO.240.157; 7.CO.240.158; 7.CO.240.196; 7.CO.240.223; 7.CO.240.240;7.CO.240.244; 7.CO.240.243; 7.CO.240.247; 7.CO.244.157; 7.CO.244.158;7.CO.244.196; 7.CO.244.223; 7.CO.244.240; 7.CO.244.244; 7.CO.244.243;7.CO.244.247; 7.CO.4.157; 7.CO.4.158; 7.CO.4.196; 7.CO.4.223;7.CO.4.240; 7.CO.4.244; 7.CO.4.243; 7.CO.4.247; Prodrugs of 8.AH8.AH.4.157; 8.AH.4.158; 8.AH.4.196; 8.AH.4.223; 8.AH.4.240; 8.AH.4.244;8.AH.4.243; 8.AH.4.247; 8.AH.5.157; 8.AH.5.158; 8.AH.5.196; 8.AH.5.223;8.AH.5.240; 8.AH.5.244; 8.AH.5.243; 8.AH.5.247; 8.AH.7.157; 8.AH.7.158;8.AH.7.196; 8.AH.7.223; 8.AH.7.240; 8.AH.7.244; 8.AH.7.243; 8.AH.7.247;8.AH.15.157; 8.AH.15.158; 8.AH.15.196; 8.AH.15.223; 8.AH.15.240;8.AH.15.244; 8.AH.15.243; 8.AH.15.247; 8.AH.16.157; 8.AH.16.158;8.AH.16.196; 8.AH.16.223; 8.AH.16.240; 8.AH.16.244; 8.AH.16.243;8.AH.16.247; 8.AH.18.157; 8.AH.18.158; 8.AH.18.196; 8.AH.18.223;8.AH.18.240; 8.AH.18.244; 8.AH.18.243; 8.AH.18.247; 8.AH.26.157;8.AH.26.158; 8.AH.26.196; 8.AH.26.223; 8.AH.26.240; 8.AH.26.244;8.AH.26.243; 8.AH.26.247; 8.AH.27.157; 8.AH.27.158; 8.AH.27.196;8.AH.27.223; 8.AH.27.240; 8.AH.27.244; 8.AH.27.243; 8.AH.27.247;8.AH.29.157; 8.AH.29.158; 8.AH.29.196; 8.AH.29.223; 8.AH.29.240;8.AH.29.244; 8.AH.29.243; 8.AH.29.247; 8.AH.54.157; 8.AH.54.158;8.AH.54.196; 8.AH.54.223; 8.AH.54.240; 8.AH.54.244; 8.AH.54.243;8.AH.54.247; 8.AH.55.157; 8.AH.55.158; 8.AH.55.196; 8.AH.55.223;8.AH.55.240; 8.AH.55.244; 8.AH.55.243; 8.AH.55.247; 8.AH.56.157;8.AH.56.158; 8.AH.56.196; 8.AH.56.223; 8.AH.56.240; 8.AH.56.244;8.AH.56.243; 8.AH.56.247; 8.AH.157.157; 8.AH.157.158; 8.AH.157.196;8.AH.157.223; 8.AH.157.240; 8.AH.157.244; 8.AH.157.243; 8.AH.157.247;8.AH.196.157; 8.AH.196.158; 8.AH.196.196; 8.AH.196.223; 8.AH.196.240;8.AH.196.244; 8.AH.196.243; 8.AH.196.247; 8.AH.223.157; 8.AH.223.158;8.AH.223.196; 8.AH.223.223; 8.AH.223.240; 8.AH.223.244; 8.AH.223.243;8.AH.223.247; 8.AH.240.157; 8.AH.240.158; 8.AH.240.196; 8.AH.240.223;8.AH.240.240; 8.AH.240.244; 8.AH.240.243; 8.AH.240.247; 8.AH.244.157;8.AH.244.158; 8.AH.244.196; 8.AH.244.223; 8.AH.244.240; 8.AH.244.244;8.AH.244.243; 8.AH.244.247; 8.AH.247.157; 8.AH.247.158; 8.AH.247.196;8.AH.247.223; 8.AH.247.240; 8.AH.247.244; 8.AH.247.243; 8.AH.247.247;Prodrugs of 8.AJ 8.AJ.4.157; 8.AJ.4.158; 8.AJ.4.196; 8.AJ.4.223;8.AJ.4.240; 8.AJ.4.244; 8.AJ.4.243; 8.AJ.4.247; 8.AJ.5.157; 8.AJ.5.158;8.AJ.5.196; 8.AJ.5.223; 8.AJ.5.240; 8.AJ.5.244; 8.AJ.5.243; 8.AJ.5.247;8.AJ.7.157; 8.AJ.7.158; 8.AJ.7.196; 8.AJ.7.223; 8.AJ.7.240; 8.AJ.7.244;8.AJ.7.243; 8.AJ.7.247; 8.AJ.15.157; 8.AJ.15.158; 8.AJ.15.196;8.AJ.15.223; 8.AJ.15.240; 8.AJ.15.244; 8.AJ.15.243; 8.AJ.15.247;8.AJ.16.157; 8.AJ.16.158; 8.AJ.16.196; 8.AJ.16.223; 8.AJ.16.240;8.AJ.16.244; 8.AJ.16.243; 8.AJ.16.247; 8.AJ.18.157; 8.AJ.18.158;8.AJ.18.196; 8.AJ.18.223; 8.AJ.18.240; 8.AJ.18.244; 8.AJ.18.243;8.AJ.18.247; 8.AJ.26.157; 8.AJ.26.158; 8.AJ.26.196; 8.AJ.26.223;8.AJ.26.240; 8.AJ.26.244; 8.AJ.26.243; 8.AJ.26.247; 8.AJ.27.157;8.AJ.27.158; 8.AJ.27.196; 8.AJ.27.223; 8.AJ.27.240; 8.AJ.27.244;8.AJ.27.243; 8.AJ.27.247; 8.AJ.29.157; 8.AJ.29.158; 8.AJ.29.196;8.AJ.29.223; 8.AJ.29.240; 8.AJ.29.244; 8.AJ.29.243; 8.AJ.29.247;8.AJ.54.157; 8.AJ.54.158; 8.AJ.54.196; 8.AJ.54.223; 8.AJ.54.240;8.AJ.54.244; 8.AJ.54.243; 8.AJ.54.247; 8.AJ.55.157; 8.AJ.55.158;8.AJ.55.196; 8.AJ.55.223; 8.AJ.55.240; 8.AJ.55.244; 8.AJ.55.243;8.AJ.55.247; 8.AJ.56.157; 8.AJ.56.158; 8.AJ.56.196; 8.AJ.56.223;8.AJ.56.240; 8.AJ.56.244; 8.AJ.56.243; 8.AJ.56.247; 8.AJ.157.157;8.AJ.157.158; 8.AJ.157.196; 8.AJ.157.223; 8.AJ.157.240; 8.AJ.157.244;8.AJ.157.243; 8.AJ.157.247; 8.AJ.196.157; 8.AJ.196.158; 8.AJ.196.196;8.AJ.196.223; 8.AJ.196.240; 8.AJ.196.244; 8.AJ.196.243; 8.AJ.196.247;8.AJ.223.157; 8.AJ.223.158; 8.AJ.223.196; 8.AJ.223.223; 8.AJ.223.240;8.AJ.223.244; 8.AJ.223.243; 8.AJ.223.247; 8.AJ.240.157; 8.AJ.240.158;8.AJ.240.196; 8.AJ.240.223; 8.AJ.240.240; 8.AJ.240.244; 8.AJ.240.243;8.AJ.240.247; 8.AJ.244.157; 8.AJ.244.158; 8.AJ.244.196; 8.AJ.244.223;8.AJ.244.240; 8.AJ.244.244; 8.AJ.244.243; 8.AJ.244.247; 8.AJ.247.157;8.AJ.247.158; 8.AJ.247.196; 8.AJ.247.223; 8.AJ.247.240; 8.AJ.247.244;8.AJ.247.243; 8.AJ.247.247; Prodrugs of 8.AN 8.AN.4.157; 8.AN.4.158;8.AN.4.196; 8.AN.4.223; 8.AN.4.240; 8.AN.4.244; 8.AN.4.243; 8.AN.4.247;8.AN.5.157; 8.AN.5.158; 8.AN.5.196; 8.AN.5.223; 8.AN.5.240; 8.AN.5.244;8.AN.5.243; 8.AN.5.247; 8.AN.7.157; 8.AN.7.158; 8.AN.7.196; 8.AN.7.223;8.AN.7.240; 8.AN.7.244; 8.AN.7.243; 8.AN.7.247; 8.AN.15.157;8.AN.15.158; 8.AN.15.196; 8.AN.15.223; 8.AN.15.240; 8.AN.15.244;8.AN.15.243; 8.AN.15.247; 8.AN.16.157; 8.AN.16.158; 8.AN.16.196;8.AN.16.223; 8.AN.16.240; 8.AN.16.244; 8.AN.16.243; 8.AN.16.247;8.AN.18.157; 8.AN.18.158; 8.AN.18.196; 8.AN.18.223; 8.AN.18.240;8.AN.18.244; 8.AN.18.243; 8.AN.18.247; 8.AN.26.157; 8.AN.26.158;8.AN.26.196; 8.AN.26.223; 8.AN.26.240; 8.AN.26.244; 8.AN.26.243;8.AN.26.247; 8.AN.27.157; 8.AN.27.158; 8.AN.27.196; 8.AN.27.223;8.AN.27.240; 8.AN.27.244; 8.AN.27.243; 8.AN.27.247; 8.AN.29.157;8.AN.29.158; 8.AN.29.196; 8.AN.29.223; 8.AN.29.240; 8.AN.29.244;8.AN.29.243; 8.AN.29.247; 8.AN.54.157; 8.AN.54.158; 8.AN.54.196;8.AN.54.223; 8.AN.54.240; 8.AN.54.244; 8.AN.54.243; 8.AN.54.247;8.AN.55.157; 8.AN.55.158; 8.AN.55.196; 8.AN.55.223; 8.AN.55.240;8.AN.55.244; 8.AN.55.243; 8.AN.55.247; 8.AN.56.157; 8.AN.56.158;8.AN.56.196; 8.AN.56.223; 8.AN.56.240; 8.AN.56.244; 8.AN.56.243;8.AN.56.247; 8.AN.157.157; 8.AN.157.158; 8.AN.157.196; 8.AN.157.223;8.AN.157.240; 8.AN.157.244; 8.AN.157.243; 8.AN.157.247; 8.AN.196.157;8.AN.196.158; 8.AN.196.196; 8.AN.196.223; 8.AN.196.240; 8.AN.196.244;8.AN.196.243; 8.AN.196.247; 8.AN.223.157; 8.AN.223.158; 8.AN.223.196;8.AN.223.223; 8.AN.223.240; 8.AN.223.244; 8.AN.223.243; 8.AN.223.247;8.AN.240.157; 8.AN.240.158; 8.AN.240.196; 8.AN.240.223; 8.AN.240.240;8.AN.240.244; 8.AN.240.243; 8.AN.240.247; 8.AN.244.157; 8.AN.244.158;8.AN.244.196; 8.AN.244.223; 8.AN.244.240; 8.AN.244.244; 8.AN.244.243;8.AN.244.247; 8.AN.247.157; 8.AN.247.158; 8.AN.247.196; 8.AN.247.223;8.AN.247.240; 8.AN.247.244; 8.AN.247.243; 8.AN.247.247; Prodrugs of 8.AP8.AP.4.157; 8.AP.4.158; 8.AP.4.196; 8.AP.4.223; 8.AP.4.240; 8.AP.4.244;8.AP.4.243; 8.AP.4.247; 8.AP.5.157; 8.AP.5.158; 8.AP.5.196; 8.AP.5.223;8.AP.5.240; 8.AP.5.244; 8.AP.5.243; 8.AP.5.247; 8.AP.7.157; 8.AP.7.158;8.AP.7.196; 8.AP.7.223; 8.AP.7.240; 8.AP.7.244; 8.AP.7.243; 8.AP.7.247;8.AP.15.157; 8.AP.15.158; 8.AP.15.196; 8.AP.15.223; 8.AP.15.240;8.AP.15.244; 8.AP.15.243; 8.AP.15.247; 8.AP.16.157; 8.AP.16.158;8.AP.16.196; 8.AP.16.223; 8.AP.16.240; 8.AP.16.244; 8.AP.16.243;8.AP.16.247; 8.AP.18.157; 8.AP.18.158; 8.AP.18.196; 8.AP.18.223;8.AP.18.240; 8.AP.18.244; 8.AP.18.243; 8.AP.18.247; 8.AP.26.157;8.AP.26.158; 8.AP.26.196; 8.AP.26.223; 8.AP.26.240; 8.AP.26.244;8.AP.26.243; 8.AP.26.247; 8.AP.27.157; 8.AP.27.158; 8.AP.27.196;8.AP.27.223; 8.AP.27.240; 8.AP.27.244; 8.AP.27.243; 8.AP.27.247;8.AP.29.157; 8.AP.29.158; 8.AP.29.196; 8.AP.29.223; 8.AP.29.240;8.AP.29.244; 8.AP.29.243; 8.AP.29.247; 8.AP.54.157; 8.AP.54.158;8.AP.54.196; 8.AP.54.223; 8.AP.54.240; 8.AP.54.244; 8.AP.54.243;8.AP.54.247; 8.AP.55.157; 8.AP.55.158; 8.AP.55.196; 8.AP.55.223;8.AP.55.240; 8.AP.55.244; 8.AP.55.243; 8.AP.55.247; 8.AP.56.157;8.AP.56.158; 8.AP.56.196; 8.AP.56.223; 8.AP.56.240; 8.AP.56.244;8.AP.56.243; 8.AP.56.247; 8.AP.157.157; 8.AP.157.158; 8.AP.157.196;8.AP.157.223; 8.AP.157.240; 8.AP.157.244; 8.AP.157.243; 8.AP.157.247;8.AP.196.157; 8.AP.196.158; 8.AP.196.196; 8.AP.196.223; 8.AP.196.240;8.AP.196.244; 8.AP.196.243; 8.AP.196.247; 8.AP.223.157; 8.AP.223.158;8.AP.223.196; 8.AP.223.223; 8.AP.223.240; 8.AP.223.244; 8.AP.223.243;8.AP.223.247; 8.AP.240.157; 8.AP.240.158; 8.AP.240.196; 8.AP.240.223;8.AP.240.240; 8.AP.240.244; 8.AP.240.243; 8.AP.240.247; 8.AP.244.157;8.AP.244.158; 8.AP.244.196; 8.AP.244.223; 8.AP.244.240; 8.AP.244.244;8.AP.244.243; 8.AP.244.247; 8.AP.247.157; 8.AP.247.158; 8.AP.247.196;8.AP.247.223; 8.AP.247.240; 8.AP.247.244; 8.AP.247.243; 8.AP.247.247;Prodrugs of 8.AZ 8.AZ.4.157; 8.AZ.4.158; 8.AZ.4.196; 8.AZ.4.223;8.AZ.4.240; 8.AZ.4.244; 8.AZ.4.243; 8.AZ.4.247; 8.AZ.5.157; 8.AZ.5.158;8.AZ.5.196; 8.AZ.5.223; 8.AZ.5.240; 8.AZ.5.244; 8.AZ.5.243; 8.AZ.5.247;8.AZ.7.157; 8.AZ.7.158; 8.AZ.7.196; 8.AZ.7.223; 8.AZ.7.240; 8.AZ.7.244;8.AZ.7.243; 8.AZ.7.247; 8.AZ.15.157; 8.AZ.15.158; 8.AZ.15.196;8.AZ.15.223; 8.AZ.15.240; 8.AZ.15.244; 8.AZ.15.243; 8.AZ.15.247;8.AZ.16.157; 8.AZ.16.158; 8.AZ.16.196; 8.AZ.16.223; 8.AZ.16.240;8.AZ.16.244; 8.AZ.16.243; 8.AZ.16.247; 8.AZ.18.157; 8.AZ.18.158;8.AZ.18.196; 8.AZ.18.223; 8.AZ.18.240; 8.AZ.18.244; 8.AZ.18.243;8.AZ.18.247; 8.AZ.26.157; 8.AZ.26.158; 8.AZ.26.196; 8.AZ.26.223;8.AZ.26.240; 8.AZ.26.244; 8.AZ.26.243; 8.AZ.26.247; 8.AZ.27.157;8.AZ.27.158; 8.AZ.27.196; 8.AZ.27.223; 8.AZ.27.240; 8.AZ.27.244;8.AZ.27.243; 8.AZ.27.247; 8.AZ.29.157; 8.AZ.29.158; 8.AZ.29.196;8.AZ.29.223; 8.AZ.29.240; 8.AZ.29.244; 8.AZ.29.243; 8.AZ.29.247;8.AZ.54.157; 8.AZ.54.158; 8.AZ.54.196; 8.AZ.54.223; 8.AZ.54.240;8.AZ.54.244; 8.AZ.54.243; 8.AZ.54.247; 8.AZ.55.157; 8.AZ.55.158;8.AZ.55.196; 8.AZ.55.223; 8.AZ.55.240; 8.AZ.55.244; 8.AZ.55.243;8.AZ.55.247; 8.AZ.56.157; 8.AZ.56.158; 8.AZ.56.196; 8.AZ.56.223;8.AZ.56.240; 8.AZ.56.244; 8.AZ.56.243; 8.AZ.56.247; 8.AZ.157.157;8.AZ.157.158; 8.AZ.157.196; 8.AZ.157.223; 8.AZ.157.240; 8.AZ.157.244;8.AZ.157.243; 8.AZ.157.247; 8.AZ.196.157; 8.AZ.196.158; 8.AZ.196.196;8.AZ.196.223; 8.AZ.196.240; 8.AZ.196.244; 8.AZ.196.243; 8.AZ.196.247;8.AZ.223.157; 8.AZ.223.158; 8.AZ.223.196; 8.AZ.223.223; 8.AZ.223.240;8.AZ.223.244; 8.AZ.223.243; 8.AZ.223.247; 8.AZ.240.157; 8.AZ.240.158;8.AZ.240.196; 8.AZ.240.223; 8.AZ.240.240; 8.AZ.240.244; 8.AZ.240.243;8.AZ.240.247; 8.AZ.244.157; 8.AZ.244.158; 8.AZ.244.196; 8.AZ.244.223;8.AZ.244.240; 8.AZ.244.244; 8.AZ.244.243; 8.AZ.244.247; 8.AZ.247.157;8.AZ.247.158; 8.AZ.247.196; 8.AZ.247.223; 8.AZ.247.240; 8.AZ.247.244;8.AZ.247.243; 8.AZ.247.247; Prodrugs of 8.BF 8.BF.4.157; 8.BF.4.158;8.BF.4.196; 8.BF.4.223; 8.BF.4.240; 8.BF.4.244; 8.BF.4.243; 8.BF.4.247;8.BF.5.157; 8.BF.5.158; 8.BF.5.196; 8.BF.5.223; 8.BF.5.240; 8.BF.5.244;8.BF.5.243; 8.BF.5.247; 8.BF.7.157; 8.BF.7.158; 8.BF.7.196; 8.BF.7.223;8.BF.7.240; 8.BF.7.244; 8.BF.7.243; 8.BF.7.247; 8.BF.15.157;8.BF.15.158; 8.BF.15.196; 8.BF.15.223; 8.BF.15.240; 8.BF.15.244;8.BF.15.243; 8.BF.15.247; 8.BF.16.157; 8.BF.16.158; 8.BF.16.196;8.BF.16.223; 8.BF.16.240; 8.BF.16.244; 8.BF.16.243; 8.BF.16.247;8.BF.18.157; 8.BF.18.158; 8.BF.18.196; 8.BF.18.223; 8.BF.18.240;8.BF.18.244; 8.BF.18.243; 8.BF.18.247; 8.BF.26.157; 8.BF.26.158;8.BF.26.196; 8.BF.26.223; 8.BF.26.240; 8.BF.26.244; 8.BF.26.243;8.BF.26.247; 8.BF.27.157; 8.BF.27.158; 8.BF.27.196; 8.BF.27.223;8.BF.27.240; 8.BF.27.244; 8.BF.27.243; 8.BF.27.247; 8.BF.29.157;8.BF.29.158; 8.BF.29.196; 8.BF.29.223; 8.BF.29.240; 8.BF.29.244;8.BF.29.243; 8.BF.29.247; 8.BF.54.157; 8.BF.54.158; 8.BF.54.196;8.BF.54.223; 8.BF.54.240; 8.BF.54.244; 8.BF.54.243; 8.BF.54.247;8.BF.55.157; 8.BF.55.158; 8.BF.55.196; 8.BF.55.223; 8.BF.55.240;8.BF.55.244; 8.BF.55.243; 8.BF.55.247; 8.BF.56.157; 8.BF.56.158;8.BF.56.196; 8.BF.56.223; 8.BF.56.240; 8.BF.56.244; 8.BF.56.243;8.BF.56.247; 8.BF.157.157; 8.BF.157.158; 8.BF.157.196; 8.BF.157.223;8.BF.157.240; 8.BF.157.244; 8.BF.157.243; 8.BF.157.247; 8.BF.196.157;8.BF.196.158; 8.BF.196.196; 8.BF.196.223; 8.BF.196.240; 8.BF.196.244;8.BF.196.243; 8.BF.196.247; 8.BF.223.157; 8.BF.223.158; 8.BF.223.196;8.BF.223.223; 8.BF.223.240; 8.BF.223.244; 8.BF.223.243; 8.BF.223.247;8.BF.240.157; 8.BF.240.158; 8.BF.240.196; 8.BF.240.223; 8.BF.240.240;8.BF.240.244; 8.BF.240.243; 8.BF.240.247; 8.BF.244.157; 8.BF.244.158;8.BF.244.196; 8.BF.244.223; 8.BF.244.240; 8.BF.244.244; 8.BF.244.243;8.BF.244.247; 8.BF.247.157; 8.BF.247.158; 8.BF.247.196; 8.BF.247.223;8.BF.247.240; 8.BF.247.244; 8.BF.247.243; 8.BF.247.247; Prodrugs of 8.CI8.CI.4.157; 8.CI.4.158; 8.CI.4.196; 8.CI.4.223; 8.CI.4.240; 8.CI.4.244;8.CI.4.243; 8.CI.4.247; 8.CI.5.157; 8.CI.5.158; 8.CI.5.196; 8.CI.5.223;8.CI.5.240; 8.CI.5.244; 8.CI.5.243; 8.CI.5.247; 8.CI.7.157; 8.CI.7.158;8.CI.7.196; 8.CI.7.223; 8.CI.7.240; 8.CI.7.244; 8.CI.7.243; 8.CI.7.247;8.CI.15.157; 8.CI.15.158; 8.CI.15.196; 8.CI.15.223; 8.CI.15.240;8.CI.15.244; 8.CI.15.243; 8.CI.15.247; 8.CI.16.157; 8.CI.16.158;8.CI.16.196; 8.CI.16.223; 8.CI.16.240; 8.CI.16.244; 8.CI.16.243;8.CI.16.247; 8.CI.18.157; 8.CI.18.158; 8.CI.18.196; 8.CI.18.223;8.CI.18.240; 8.CI.18.244; 8.CI.18.243; 8.CI.18.247; 8.CI.26.157;8.CI.26.158; 8.CI.26.196; 8.CI.26.223; 8.CI.26.240; 8.CI.26.244;8.CI.26.243; 8.CI.26.247; 8.CI.27.157; 8.CI.27.158; 8.CI.27.196;8.CI.27.223; 8.CI.27.240; 8.CI.27.244; 8.CI.27.243; 8.CI.27.247;8.CI.29.157; 8.CI.29.158; 8.CI.29.196; 8.CI.29.223; 8.CI.29.240;8.CI.29.244; 8.CI.29.243; 8.CI.29.247; 8.CI.54.157; 8.CI.54.158;8.CI.54.196; 8.CI.54.223; 8.CI.54.240; 8.CI.54.244; 8.CI.54.243;8.CI.54.247; 8.CI.55.157; 8.CI.55.158; 8.CI.55.196; 8.CI.55.223;8.CI.55.240; 8.CI.55.244; 8.CI.55.243; 8.CI.55.247; 8.CI.56.157;8.CI.56.158; 8.CI.56.196; 8.CI.56.223; 8.CI.56.240; 8.CI.56.244;8.CI.56.243; 8.CI.56.247; 8.CI.157.157; 8.CI.157.158; 8.CI.157.196;8.CI.157.223; 8.CI.157.240; 8.CI.157.244; 8.CI.157.243; 8.CI.157.247;8.CI.196.157; 8.CI.196.158; 8.CI.196.196; 8.CI.196.223; 8.CI.196.240;8.CI.196.244; 8.CI.196.243; 8.CI.196.247; 8.CI.223.157; 8.CI.223.158;8.CI.223.196; 8.CI.223.223; 8.CI.223.240; 8.CI.223.244; 8.CI.223.243;8.CI.223.247; 8.CI.240.157; 8.CI.240.158; 8.CI.240.196; 8.CI.240.223;8.CI.240.240; 8.CI.240.244; 8.CI.240.243; 8.CI.240.247; 8.CI.244.157;8.CI.244.158; 8.CI.244.196; 8.CI.244.223; 8.CI.244.240; 8.CI.244.244;8.CI.244.243; 8.CI.244.247; 8.CI.247.157; 8.CI.247.158; 8.CI.247.196;8.CI.247.223; 8.CI.247.240; 8.CI.247.244; 8.CI.247.243; 8.CI.247.247;Prodrugs of 8.CO 8.CO.4.157; 8.CO.4.158; 8.CO.4.196; 8.CO.4.223;8.CO.4.240; 8.CO.4.244; 8.CO.4.243; 8.CO.4.247; 8.CO.5.157; 8.CO.5.158;8.CO.5.196; 8.CO.5.223; 8.CO.5.240; 8.CO.5.244; 8.CO.5.243; 8.CO.5.247;8.CO.7.157; 8.CO.7.158; 8.CO.7.196; 8.CO.7.223; 8.CO.7.240; 8.CO.7.244;8.CO.7.243; 8.CO.7.247; 8.CO.15.157; 8.CO.15.158; 8.CO.15.196;8.CO.15.223; 8.CO.15.240; 8.CO.15.244; 8.CO.15.243; 8.CO.15.247;8.CO.16.157; 8.CO.16.158; 8.CO.16.196; 8.CO.16.223; 8.CO.16.240;8.CO.16.244; 8.CO.16.243; 8.CO.16.247; 8.CO.18.157; 8.CO.18.158;8.CO.18.196; 8.CO.18.223; 8.CO.18.240; 8.CO.18.244; 8.CO.18.243;8.CO.18.247; 8.CO.26.157; 8.CO.26.158; 8.CO.26.196; 8.CO.26.223;8.CO.26.240; 8.CO.26.244; 8.CO.26.243; 8.CO.26.247; 8.CO.27.157;8.CO.27.158; 8.CO.27.196; 8.CO.27.223; 8.CO.27.240; 8.CO.27.244;8.CO.27.243; 8.CO.27.247; 8.CO.29.157; 8.CO.29.158; 8.CO.29.196;8.CO.29.223; 8.CO.29.240; 8.CO.29.244; 8.CO.29.243; 8.CO.29.247;8.CO.54.157; 8.CO.54.158; 8.CO.54.196; 8.CO.54.223; 8.CO.54.240;8.CO.54.244; 8.CO.54.243; 8.CO.54.247; 8.CO.55.157; 8.CO.55.158;8.CO.55.196; 8.CO.55.223; 8.CO.55.240; 8.CO.55.244; 8.CO.55.243;8.CO.55.247; 8.CO.56.157; 8.CO.56.158; 8.CO.56.196; 8.CO.56.223;8.CO.56.240; 8.CO.56.244; 8.CO.56.243; 8.CO.56.247; 8.CO.157.157;8.CO.157.158; 8.CO.157.196; 8.CO.157.223; 8.CO.157.240; 8.CO.157.244;8.CO.157.243; 8.CO.157.247; 8.CO.196.157; 8.CO.196.158; 8.CO.196.196;8.CO.196.223; 8.CO.196.240; 8.CO.196.244; 8.CO.196.243; 8.CO.196.247;8.CO.223.157; 8.CO.223.158; 8.CO.223.196; 8.CO.223.223; 8.CO.223.240;8.CO.223.244; 8.CO.223.243; 8.CO.223.247; 8.CO.240.157; 8.CO.240.158;8.CO.240.196; 8.CO.240.223; 8.CO.240.240; 8.CO.240.244; 8.CO.240.243;8.CO.240.247; 8.CO.244.157; 8.CO.244.158; 8.CO.244.196; 8.CO.244.223;8.CO.244.240; 8.CO.244.244; 8.CO.244.243; 8.CO.244.247; 8.CO.247.157;8.CO.247.158; 8.CO.247.196; 8.CO.247.223; 8.CO.247.240; 8.CO.247.244;8.CO.247.243; 8.CO.247.247; Prodrugs of 9.AH 9.AH.4.157; 9.AH.4.158;9.AH.4.196; 9.AH.4.223; 9.AH.4.240; 9.AH.4.244; 9.AH.4.243; 9.AH.4.247;9.AH.5.157; 9.AH.5.158; 9.AH.5.196; 9.AH.5.223; 9.AH.5.240; 9.AH.5.244;9.AH.5.243; 9.AH.5.247; 9.AH.7.157; 9.AH.7.158; 9.AH.7.196; 9.AH.7.223;9.AH.7.240; 9.AH.7.244; 9.AH.7.243; 9.AH.7.247; 9.AH.15.157;9.AH.15.158; 9.AH.15.196; 9.AH.15.223; 9.AH.15.240; 9.AH.15.244;9.AH.15.243; 9.AH.15.247; 9.AH.16.157; 9.AH.16.158; 9.AH.16.196;9.AH.16.223; 9.AH.16.240; 9.AH.16.244; 9.AH.16.243; 9.AH.16.247;9.AH.18.157; 9.AH.18.158; 9.AH.18.196; 9.AH.18.223; 9.AH.18.240;9.AH.18.244; 9.AH.18.243; 9.AH.18.247; 9.AH.26.157; 9.AH.26.158;9.AH.26.196; 9.AH.26.223; 9.AH.26.240; 9.AH.26.244; 9.AH.26.243;9.AH.26.247; 9.AH.27.157; 9.AH.27.158; 9.AH.27.196; 9.AH.27.223;9.AH.27.240; 9.AH.27.244; 9.AH.27.243; 9.AH.27.247; 9.AH.29.157;9.AH.29.158; 9.AH.29.196; 9.AH.29.223; 9.AH.29.240; 9.AH.29.244;9.AH.29.243; 9.AH.29.247; 9.AH.54.157; 9.AH.54.158; 9.AH.54.196;9.AH.54.223; 9.AH.54.240; 9.AH.54.244; 9.AH.54.243; 9.AH.54.247;9.AH.55.157; 9.AH.55.158; 9.AH.55.196; 9.AH.55.223; 9.AH.55.240;9.AH.55.244; 9.AH.55.243; 9.AH.55.247; 9.AH.56.157; 9.AH.56.158;9.AH.56.196; 9.AH.56.223; 9.AH.56.240; 9.AH.56.244; 9.AH.56.243;9.AH.56.247; 9.AH.157.157; 9.AH.157.158; 9.AH.157.196; 9.AH.157.223;9.AH.157.240; 9.AH.157.244; 9.AH.157.243; 9.AH.157.247; 9.AH.196.157;9.AH.196.158; 9.AH.196.196; 9.AH.196.223; 9.AH.196.240; 9.AH.196.244;9.AH.196.243; 9.AH.196.247; 9.AH.223.157; 9.AH.223.158; 9.AH.223.196;9.AH.223.223; 9.AH.223.240; 9.AH.223.244; 9.AH.223.243; 9.AH.223.247;9.AH.240.157; 9.AH.240.158; 9.AH.240.196; 9.AH.240.223; 9.AH.240.240;9.AH.240.244; 9.AH.240.243; 9.AH.240.247; 9.AH.244.157; 9.AH.244.158;9.AH.244.196; 9.AH.244.223; 9.AH.244.240; 9.AH.244.244; 9.AH.244.243;9.AH.244.247; 9.AH.247.157; 9.AH.247.158; 9.AH.247.196; 9.AH.247.223;9.AH.247.240; 9.AH.247.244; 9.AH.247.243; 9.AH.247.247; Prodrugs of 9.AJ9.AJ.4.157; 9.AJ.4.158; 9.AJ.4.196; 9.AJ.4.223; 9.AJ.4.240; 9.AJ.4.244;9.AJ.4.243; 9.AJ.4.247; 9.AJ.5.157; 9.AJ.5.158; 9.AJ.5.196; 9.AJ.5.223;9.AJ.5.240; 9.AJ.5.244; 9.AJ.5.243; 9.AJ.5.247; 9.AJ.7.157; 9.AJ.7.158;9.AJ.7.196; 9.AJ.7.223; 9.AJ.7.240; 9.AJ.7.244; 9.AJ.7.243; 9.AJ.7.247;9.AJ.15.157; 9.AJ.15.158; 9.AJ.15.196; 9.AJ.15.223; 9.AJ.15.240;9.AJ.15.244; 9.AJ.15.243; 9.AJ.15.247; 9.AJ.16.157; 9.AJ.16.158;9.AJ.16.196; 9.AJ.16.223; 9.AJ.16.240; 9.AJ.16.244; 9.AJ.16.243;9.AJ.16.247; 9.AJ.18.157; 9.AJ.18.158; 9.AJ.18.196; 9.AJ.18.223;9.AJ.18.240; 9.AJ.18.244; 9.AJ.18.243; 9.AJ.18.247; 9.AJ.26.157;9.AJ.26.158; 9.AJ.26.196; 9.AJ.26.223; 9.AJ.26.240; 9.AJ.26.244;9.AJ.26.243; 9.AJ.26.247; 9.AJ.27.157; 9.AJ.27.158; 9.AJ.27.196;9.AJ.27.223; 9.AJ.27.240; 9.AJ.27.244; 9.AJ.27.243; 9.AJ.27.247;9.AJ.29.157; 9.AJ.29.158; 9.AJ.29.196; 9.AJ.29.223; 9.AJ.29.240;9.AJ.29.244; 9.AJ.29.243; 9.AJ.29.247; 9.AJ.54.157; 9.AJ.54.158;9.AJ.54.196; 9.AJ.54.223; 9.AJ.54.240; 9.AJ.54.244; 9.AJ.54.243;9.AJ.54.247; 9.AJ.55.157; 9.AJ.55.158; 9.AJ.55.196; 9.AJ.55.223;9.AJ.55.240; 9.AJ.55.244; 9.AJ.55.243; 9.AJ.55.247; 9.AJ.56.157;9.AJ.56.158; 9.AJ.56.196; 9.AJ.56.223; 9.AJ.56.240; 9.AJ.56.244;9.AJ.56.243; 9.AJ.56.247; 9.AJ.157.157; 9.AJ.157.158; 9.AJ.157.196;9.AJ.157.223; 9.AJ.157.240; 9.AJ.157.244; 9.AJ.157.243; 9.AJ.157.247;9.AJ.196.157; 9.AJ.196.158; 9.AJ.196.196; 9.AJ.196.223; 9.AJ.196.240;9.AJ.196.244; 9.AJ.196.243; 9.AJ.196.247; 9.AJ.223.157; 9.AJ.223.158;9.AJ.223.196; 9.AJ.223.223; 9.AJ.223.240; 9.AJ.223.244; 9.AJ.223.243;9.AJ.223.247; 9.AJ.240.157; 9.AJ.240.158; 9.AJ.240.196; 9.AJ.240.223;9.AJ.240.240; 9.AJ.240.244; 9.AJ.240.243; 9.AJ.240.247; 9.AJ.244.157;9.AJ.244.158; 9.AJ.244.196; 9.AJ.244.223; 9.AJ.244.240; 9.AJ.244.244;9.AJ.244.243; 9.AJ.244.247; 9.AJ.247.157; 9.AJ.247.158; 9.AJ.247.196;9.AJ.247.223; 9.AJ.247.240; 9.AJ.247.244; 9.AJ.247.243; 9.AJ.247.247;Prodrugs of 9.AN 9.AN.4.157; 9.AN.4.158; 9.AN.4.196; 9.AN.4.223;9.AN.4.240; 9.AN.4.244; 9.AN.4.243; 9.AN.4.247; 9.AN.5.157; 9.AN.5.158;9.AN.5.196; 9.AN.5.223; 9.AN.5.240; 9.AN.5.244; 9.AN.5.243; 9.AN.5.247;9.AN.7.157; 9.AN.7.158; 9.AN.7.196; 9.AN.7.223; 9.AN.7.240; 9.AN.7.244;9.AN.7.243; 9.AN.7.247; 9.AN.15.157; 9.AN.15.158; 9.AN.15.196;9.AN.15.223; 9.AN.15.240; 9.AN.15.244; 9.AN.15.243; 9.AN.15.247;9.AN.16.157; 9.AN.16.158; 9.AN.16.196; 9.AN.16.223; 9.AN.16.240;9.AN.16.244; 9.AN.16.243; 9.AN.16.247; 9.AN.18.157; 9.AN.18.158;9.AN.18.196; 9.AN.18.223; 9.AN.18.240; 9.AN.18.244; 9.AN.18.243;9.AN.18.247; 9.AN.26.157; 9.AN.26.158; 9.AN.26.196; 9.AN.26.223;9.AN.26.240; 9.AN.26.244; 9.AN.26.243; 9.AN.26.247; 9.AN.27.157;9.AN.27.158; 9.AN.27.196; 9.AN.27.223; 9.AN.27.240; 9.AN.27.244;9.AN.27.243; 9.AN.27.247; 9.AN.29.157; 9.AN.29.158; 9.AN.29.196;9.AN.29.223; 9.AN.29.240; 9.AN.29.244; 9.AN.29.243; 9.AN.29.247;9.AN.54.157; 9.AN.54.158; 9.AN.54.196; 9.AN.54.223; 9.AN.54.240;9.AN.54.244; 9.AN.54.243; 9.AN.54.247; 9.AN.55.157; 9.AN.55.158;9.AN.55.196; 9.AN.55.223; 9.AN.55.240; 9.AN.55.244; 9.AN.55.243;9.AN.55.247; 9.AN.56.157; 9.AN.56.158; 9.AN.56.196; 9.AN.56.223;9.AN.56.240; 9.AN.56.244; 9.AN.56.243; 9.AN.56.247; 9.AN.157.157;9.AN.157.158; 9.AN.157.196; 9.AN.157.223; 9.AN.157.240; 9.AN.157.244;9.AN.157.243; 9.AN.157.247; 9.AN.196.157; 9.AN.196.158; 9.AN.196.196;9.AN.196.223; 9.AN.196.240; 9.AN.196.244; 9.AN.196.243; 9.AN.196.247;9.AN.223.157; 9.AN.223.158; 9.AN.223.196; 9.AN.223.223; 9.AN.223.240;9.AN.223.244; 9.AN.223.243; 9.AN.223.247; 9.AN.240.157; 9.AN.240.158;9.AN.240.196; 9.AN.240.223; 9.AN.240.240; 9.AN.240.244; 9.AN.240.243;9.AN.240.247; 9.AN.244.157; 9.AN.244.158; 9.AN.244.196; 9.AN.244.223;9.AN.244.240; 9.AN.244.244; 9.AN.244.243; 9.AN.244.247; 9.AN.247.157;9.AN.247.158; 9.AN.247.196; 9.AN.247.223; 9.AN.247.240; 9.AN.247.244;9.AN.247.243; 9.AN.247.247; Prodrugs of 9.AP 9.AP.4.157; 9.AP.4.158;9.AP.4.196; 9.AP.4.223; 9.AP.4.240; 9.AP.4.244; 9.AP.4.243; 9.AP.4.247;9.AP.5.157; 9.AP.5.158; 9.AP.5.196; 9.AP.5.223; 9.AP.5.240; 9.AP.5.244;9.AP.5.243; 9.AP.5.247; 9.AP.7.157; 9.AP.7.158; 9.AP.7.196; 9.AP.7.223;9.AP.7.240; 9.AP.7.244; 9.AP.7.243; 9.AP.7.247; 9.AP.15.157;9.AP.15.158; 9.AP.15.196; 9.AP.15.223; 9.AP.15.240; 9.AP.15.244;9.AP.15.243; 9.AP.15.247; 9.AP.16.157; 9.AP.16.158; 9.AP.16.196;9.AP.16.223; 9.AP.16.240; 9.AP.16.244; 9.AP.16.243; 9.AP.16.247;9.AP.18.157; 9.AP.18.158; 9.AP.18.196; 9.AP.18.223; 9.AP.18.240;9.AP.18.244; 9.AP.18.243; 9.AP.18.247; 9.AP.26.157; 9.AP.26.158;9.AP.26.196; 9.AP.26.223; 9.AP.26.240; 9.AP.26.244; 9.AP.26.243;9.AP.26.247; 9.AP.27.157; 9.AP.27.158; 9.AP.27.196; 9.AP.27.223;9.AP.27.240; 9.AP.27.244; 9.AP.27.243; 9.AP.27.247; 9.AP.29.157;9.AP.29.158; 9.AP.29.196; 9.AP.29.223; 9.AP.29.240; 9.AP.29.244;9.AP.29.243; 9.AP.29.247; 9.AP.54.157; 9.AP.54.158; 9.AP.54.196;9.AP.54.223; 9.AP.54.240; 9.AP.54.244; 9.AP.54.243; 9.AP.54.247;9.AP.55.157; 9.AP.55.158; 9.AP.55.196; 9.AP.55.223; 9.AP.55.240;9.AP.55.244; 9.AP.55.243; 9.AP.55.247; 9.AP.56.157; 9.AP.56.158;9.AP.56.196; 9.AP.56.223; 9.AP.56.240; 9.AP.56.244; 9.AP.56.243;9.AP.56.247; 9.AP.157.157; 9.AP.157.158; 9.AP.157.196; 9.AP.157.223;9.AP.157.240; 9.AP.157.244; 9.AP.157.243; 9.AP.157.247; 9.AP.196.157;9.AP.196.158; 9.AP.196.196; 9.AP.196.223; 9.AP.196.240; 9.AP.196.244;9.AP.196.243; 9.AP.196.247; 9.AP.223.157; 9.AP.223.158; 9.AP.223.196;9.AP.223.223; 9.AP.223.240; 9.AP.223.244; 9.AP.223.243; 9.AP.223.247;9.AP.240.157; 9.AP.240.158; 9.AP.240.196; 9.AP.240.223; 9.AP.240.240;9.AP.240.244; 9.AP.240.243; 9.AP.240.247; 9.AP.244.157; 9.AP.244.158;9.AP.244.196; 9.AP.244.223; 9.AP.244.240; 9.AP.244.244; 9.AP.244.243;9.AP.244.247; 9.AP.247.157; 9.AP.247.158; 9.AP.247.196; 9.AP.247.223;9.AP.247.240; 9.AP.247.244; 9.AP.247.243; 9.AP.247.247; Prodrugs of 9.AZ9.AZ.4.157; 9.AZ.4.158; 9.AZ.4.196; 9.AZ.4.223; 9.AZ.4.240; 9.AZ.4.244;9.AZ.4.243; 9.AZ.4.247; 9.AZ.5.157; 9.AZ.5.158; 9.AZ.5.196; 9.AZ.5.223;9.AZ.5.240; 9.AZ.5.244; 9.AZ.5.243; 9.AZ.5.247; 9.AZ.7.157; 9.AZ.7.158;9.AZ.7.196; 9.AZ.7.223; 9.AZ.7.240; 9.AZ.7.244; 9.AZ.7.243; 9.AZ.7.247;9.AZ.15.157; 9.AZ.15.158; 9.AZ.15.196; 9.AZ.15.223; 9.AZ.15.240;9.AZ.15.244; 9.AZ.15.243; 9.AZ.15.247; 9.AZ.16.157; 9.AZ.16.158;9.AZ.16.196; 9.AZ.16.223; 9.AZ.16.240; 9.AZ.16.244; 9.AZ.16.243;9.AZ.16.247; 9.AZ.18.157; 9.AZ.18.158; 9.AZ.18.196; 9.AZ.18.223;9.AZ.18.240; 9.AZ.18.244; 9.AZ.18.243; 9.AZ.18.247; 9.AZ.26.157;9.AZ.26.158; 9.AZ.26.196; 9.AZ.26.223; 9.AZ.26.240; 9.AZ.26.244;9.AZ.26.243; 9.AZ.26.247; 9.AZ.27.157; 9.AZ.27.158; 9.AZ.27.196;9.AZ.27.223; 9.AZ.27.240; 9.AZ.27.244; 9.AZ.27.243; 9.AZ.27.247;9.AZ.29.157; 9.AZ.29.158; 9.AZ.29.196; 9.AZ.29.223; 9.AZ.29.240;9.AZ.29.244; 9.AZ.29.243; 9.AZ.29.247; 9.AZ.54.157; 9.AZ.54.158;9.AZ.54.196; 9.AZ.54.223; 9.AZ.54.240; 9.AZ.54.244; 9.AZ.54.243;9.AZ.54.247; 9.AZ.55.157; 9.AZ.55.158; 9.AZ.55.196; 9.AZ.55.223;9.AZ.55.240; 9.AZ.55.244; 9.AZ.55.243; 9.AZ.55.247; 9.AZ.56.157;9.AZ.56.158; 9.AZ.56.196; 9.AZ.56.223; 9.AZ.56.240; 9.AZ.56.244;9.AZ.56.243; 9.AZ.56.247; 9.AZ.157.157; 9.AZ.157.158; 9.AZ.157.196;9.AZ.157.223; 9.AZ.157.240; 9.AZ.157.244; 9.AZ.157.243; 9.AZ.157.247;9.AZ.196.157; 9.AZ.196.158; 9.AZ.196.196; 9.AZ.196.223; 9.AZ.196.240;9.AZ.196.244; 9.AZ.196.243; 9.AZ.196.247; 9.AZ.223.157; 9.AZ.223.158;9.AZ.223.196; 9.AZ.223.223; 9.AZ.223.240; 9.AZ.223.244; 9.AZ.223.243;9.AZ.223.247; 9.AZ.240.157; 9.AZ.240.158; 9.AZ.240.196; 9.AZ.240.223;9.AZ.240.240; 9.AZ.240.244; 9.AZ.240.243; 9.AZ.240.247; 9.AZ.244.157;9.AZ.244.158; 9.AZ.244.196; 9.AZ.244.223; 9.AZ.244.240; 9.AZ.244.244;9.AZ.244.243; 9.AZ.244.247; 9.AZ.247.157; 9.AZ.247.158; 9.AZ.247.196;9.AZ.247.223; 9.AZ.247.240; 9.AZ.247.244; 9.AZ.247.243; 9.AZ.247.247;Prodrugs of 9.BF 9.BF.4.157; 9.BF.4.158; 9.BF.4.196; 9.BF.4.223;9.BF.4.240; 9.BF.4.244; 9.BF.4.243; 9.BF.4.247; 9.BF.5.157; 9.BF.5.158;9.BF.5.196; 9.BF.5.223; 9.BF.5.240; 9.BF.5.244; 9.BF.5.243; 9.BF.5.247;9.BF.7.157; 9.BF.7.158; 9.BF.7.196; 9.BF.7.223; 9.BF.7.240; 9.BF.7.244;9.BF.7.243; 9.BF.7.247; 9.BF.15.157; 9.BF.15.158; 9.BF.15.196;9.BF.15.223; 9.BF.15.240; 9.BF.15.244; 9.BF.15.243; 9.BF.15.247;9.BF.16.157; 9.BF.16.158; 9.BF.16.196; 9.BF.16.223; 9.BF.16.240;9.BF.16.244; 9.BF.16.243; 9.BF.16.247; 9.BF.18.157; 9.BF.18.158;9.BF.18.196; 9.BF.18.223; 9.BF.18.240; 9.BF.18.244; 9.BF.18.243;9.BF.18.247; 9.BF.26.157; 9.BF.26.158; 9.BF.26.196; 9.BF.26.223;9.BF.26.240; 9.BF.26.244; 9.BF.26.243; 9.BF.26.247; 9.BF.27.157;9.BF.27.158; 9.BF.27.196; 9.BF.27.223; 9.BF.27.240; 9.BF.27.244;9.BF.27.243; 9.BF.27.247; 9.BF.29.157; 9.BF.29.158; 9.BF.29.196;9.BF.29.223; 9.BF.29.240; 9.BF.29.244; 9.BF.29.243; 9.BF.29.247;9.BF.54.157; 9.BF.54.158; 9.BF.54.196; 9.BF.54.223; 9.BF.54.240;9.BF.54.244; 9.BF.54.243; 9.BF.54.247; 9.BF.55.157; 9.BF.55.158;9.BF.55.196; 9.BF.55.223; 9.BF.55.240; 9.BF.55.244; 9.BF.55.243;9.BF.55.247; 9.BF.56.157; 9.BF.56.158; 9.BF.56.196; 9.BF.56.223;9.BF.56.240; 9.BF.56.244; 9.BF.56.243; 9.BF.56.247; 9.BF.157.157;9.BF.157.158; 9.BF.157.196; 9.BF.157.223; 9.BF.157.240; 9.BF.157.244;9.BF.157.243; 9.BF.157.247; 9.BF.196.157; 9.BF.196.158; 9.BF.196.196;9.BF.196.223; 9.BF.196.240; 9.BF.196.244; 9.BF.196.243; 9.BF.196.247;9.BF.223.157; 9.BF.223.158; 9.BF.223.196; 9.BF.223.223; 9.BF.223.240;9.BF.223.244; 9.BF.223.243; 9.BF.223.247; 9.BF.240.157; 9.BF.240.158;9.BF.240.196; 9.BF.240.223; 9.BF.240.240; 9.BF.240.244; 9.BF.240.243;9.BF.240.247; 9.BF.244.157; 9.BF.244.158; 9.BF.244.196; 9.BF.244.223;9.BF.244.240; 9.BF.244.244; 9.BF.244.243; 9.BF.244.247; 9.BF.247.157;9.BF.247.158; 9.BF.247.196; 9.BF.247.223; 9.BF.247.240; 9.BF.247.244;9.BF.247.243; 9.BF.247.247; Prodrugs of 9.CI 9.CI.4.157; 9.CI.4.158;9.CI.4.196; 9.CI.4.223; 9.CI.4.240; 9.CI.4.244; 9.CI.4.243; 9.CI.4.247;9.CI.5.157; 9.CI.5.158; 9.CI.5.196; 9.CI.5.223; 9.CI.5.240; 9.CI.5.244;9.CI.5.243; 9.CI.5.247; 9.CI.7.157; 9.CI.7.158; 9.CI.7.196; 9.CI.7.223;9.CI.7.240; 9.CI.7.244; 9.CI.7.243; 9.CI.7.247; 9.CI.15.157;9.CI.15.158; 9.CI.15.196; 9.CI.15.223; 9.CI.15.240; 9.CI.15.244;9.CI.15.243; 9.CI.15.247; 9.CI.16.157; 9.CI.16.158; 9.CI.16.196;9.CI.16.223; 9.CI.16.240; 9.CI.16.244; 9.CI.16.243; 9.CI.16.247;9.CI.18.157; 9.CI.18.158; 9.CI.18.196; 9.CI.18.223; 9.CI.18.240;9.CI.18.244; 9.CI.18.243; 9.CI.18.247; 9.CI.26.157; 9.CI.26.158;9.CI.26.196; 9.CI.26.223; 9.CI.26.240; 9.CI.26.244; 9.CI.26.243;9.CI.26.247; 9.CI.27.157; 9.CI.27.158; 9.CI.27.196; 9.CI.27.223;9.CI.27.240; 9.CI.27.244; 9.CI.27.243; 9.CI.27.247; 9.CI.29.157;9.CI.29.158; 9.CI.29.196; 9.CI.29.223; 9.CI.29.240; 9.CI.29.244;9.CI.29.243; 9.CI.29.247; 9.CI.54.157; 9.CI.54.158; 9.CI.54.196;9.CI.54.223; 9.CI.54.240; 9.CI.54.244; 9.CI.54.243; 9.CI.54.247;9.CI.55.157; 9.CI.55.158; 9.CI.55.196; 9.CI.55.223; 9.CI.55.240;9.CI.55.244; 9.CI.55.243; 9.CI.55.247; 9.CI.56.157; 9.CI.56.158;9.CI.56.196; 9.CI.56.223; 9.CI.56.240; 9.CI.56.244; 9.CI.56.243;9.CI.56.247; 9.CI.157.157; 9.CI.157.158; 9.CI.157.196; 9.CI.157.223;9.CI.157.240; 9.CI.157.244; 9.CI.157.243; 9.CI.157.247; 9.CI.196.157;9.CI.196.158; 9.CI.196.196; 9.CI.196.223; 9.CI.196.240; 9.CI.196.244;9.CI.196.243; 9.CI.196.247; 9.CI.223.157; 9.CI.223.158; 9.CI.223.196;9.CI.223.223; 9.CI.223.240; 9.CI.223.244; 9.CI.223.243; 9.CI.223.247;9.CI.240.157; 9.CI.240.158; 9.CI.240.196; 9.CI.240.223; 9.CI.240.240;9.CI.240.244; 9.CI.240.243; 9.CI.240.247; 9.CI.244.157; 9.CI.244.158;9.CI.244.196; 9.CI.244.223; 9.CI.244.240; 9.CI.244.244; 9.CI.244.243;9.CI.244.247; 9.CI.247.157; 9.CI.247.158; 9.CI.247.196; 9.CI.247.223;9.CI.247.240; 9.CI.247.244; 9.CI.247.243; 9.CI.247.247; Prodrugs of 9.CO9.CO.4.157; 9.CO.4.158; 9.CO.4.196; 9.CO.4.223; 9.CO.4.240; 9.CO.4.244;9.CO.4.243; 9.CO.4.247; 9.CO.5.157; 9.CO.5.158; 9.CO.5.196; 9.CO.5.223;9.CO.5.240; 9.CO.5.244; 9.CO.5.243; 9.CO.5.247; 9.CO.7.157; 9.CO.7.158;9.CO.7.196; 9.CO.7.223; 9.CO.7.240; 9.CO.7.244; 9.CO.7.243; 9.CO.7.247;9.CO.15.157; 9.CO.15.158; 9.CO.15.196; 9.CO.15.223; 9.CO.15.240;9.CO.15.244; 9.CO.15.243; 9.CO.15.247; 9.CO.16.157; 9.CO.16.158;9.CO.16.196; 9.CO.16.223; 9.CO.16.240; 9.CO.16.244; 9.CO.16.243;9.CO.16.247; 9.CO.18.157; 9.CO.18.158; 9.CO.18.196; 9.CO.18.223;9.CO.18.240; 9.CO.18.244; 9.CO.18.243; 9.CO.18.247; 9.CO.26.157;9.CO.26.158; 9.CO.26.196; 9.CO.26.223; 9.CO.26.240; 9.CO.26.244;9.CO.26.243; 9.CO.26.247; 9.CO.27.157; 9.CO.27.158; 9.CO.27.196;9.CO.27.223; 9.CO.27.240; 9.CO.27.244; 9.CO.27.243; 9.CO.27.247;9.CO.29.157; 9.CO.29.158; 9.CO.29.196; 9.CO.29.223; 9.CO.29.240;9.CO.29.244; 9.CO.29.243; 9.CO.29.247; 9.CO.54.157; 9.CO.54.158;9.CO.54.196; 9.CO.54.223; 9.CO.54.240; 9.CO.54.244; 9.CO.54.243;9.CO.54.247; 9.CO.55.157; 9.CO.55.158; 9.CO.55.196; 9.CO.55.223;9.CO.55.240; 9.CO.55.244; 9.CO.55.243; 9.CO.55.247; 9.CO.56.157;9.CO.56.158; 9.CO.56.196; 9.CO.56.223; 9.CO.56.240; 9.CO.56.244;9.CO.56.243; 9.CO.56.247; 9.CO.157.157; 9.CO.157.158; 9.CO.157.196;9.CO.157.223; 9.CO.157.240; 9.CO.157.244; 9.CO.157.243; 9.CO.157.247;9.CO.196.157; 9.CO.196.158; 9.CO.196.196; 9.CO.196.223; 9.CO.196.240;9.CO.196.244; 9.CO.196.243; 9.CO.196.247; 9.CO.223.157; 9.CO.223.158;9.CO.223.196; 9.CO.223.223; 9.CO.223.240; 9.CO.223.244; 9.CO.223.243;9.CO.223.247; 9.CO.240.157; 9.CO.240.158; 9.CO.240.196; 9.CO.240.223;9.CO.240.240; 9.CO.240.244; 9.CO.240.243; 9.CO.240.247; 9.CO.244.157;9.CO.244.158; 9.CO.244.196; 9.CO.244.223; 9.CO.244.240; 9.CO.244.244;9.CO.244.243; 9.CO.244.247; 9.CO.247.157; 9.CO.247.158; 9.CO.247.196;9.CO.247.223; 9.CO.247.240; 9.CO.247.244; 9.CO.247.243; 9.CO.247.247;Prodrugs of 10.AH 10.AH.4.157; 10.AH.4.158; 10.AH.4.196; 10.AH.4.223;10.AH.4.240; 10.AH.4.244; 10.AH.4.243; 10.AH.4.247; 10.AH.5.157;10.AH.5.158; 10.AH.5.196; 10.AH.5.223; 10.AH.5.240; 10.AH.5.244;10.AH.5.243; 10.AH.5.247; 10.AH.7.157; 10.AH.7.158; 10.AH.7.196;10.AH.7.223; 10.AH.7.240; 10.AH.7.244; 10.AH.7.243; 10.AH.7.247;10.AH.15.157; 10.AH.15.158; 10.AH.15.196; 10.AH.15.223; 10.AH.15.240;10.AH.15.244; 10.AH.15.243; 10.AH.15.247; 10.AH.16.157; 10.AH.16.158;10.AH.16.196; 10.AH.16.223; 10.AH.16.240; 10.AH.16.244; 10.AH.16.243;10.AH.16.247; 10.AH.18.157; 10.AH.18.158; 10.AH.18.196; 10.AH.18.223;10.AH.18.240; 10.AH.18.244; 10.AH.18.243; 10.AH.18.247; 10.AH.26.157;10.AH.26.158; 10.AH.26.196; 10.AH.26.223; 10.AH.26.240; 10.AH.26.244;10.AH.26.243; 10.AH.26.247; 10.AH.27.157; 10.AH.27.158; 10.AH.27.196;10.AH.27.223; 10.AH.27.240; 10.AH.27.244; 10.AH.27.243; 10.AH.27.247;10.AH.29.157; 10.AH.29.158; 10.AH.29.196; 10.AH.29.223; 10.AH.29.240;10.AH.29.244; 10.AH.29.243; 10.AH.29.247; 10.AH.54.157; 10.AH.54.158;10.AH.54.196; 10.AH.54.223; 10.AH.54.240; 10.AH.54.244; 10.AH.54.243;10.AH.54.247; 10.AH.55.157; 10.AH.55.158; 10.AH.55.196; 10.AH.55.223;10.AH.55.240; 10.AH.55.244; 10.AH.55.243; 10.AH.55.247; 10.AH.56.157;10.AH.56.158; 10.AH.56.196; 10.AH.56.223; 10.AH.56.240; 10.AH.56.244;10.AH.56.243; 10.AH.56.247; 10.AH.157.157; 10.AH.157.158; 10.AH.157.196;10.AH.157.223; 10.AH.157.240; 10.AH.157.244; 10.AH.157.243;10.AH.157.247; 10.AH.196.157; 10.AH.196.158; 10.AH.196.196;10.AH.196.223; 10.AH.196.240; 10.AH.196.244; 10.AH.196.243;10.AH.196.247; 10.AH.223.157; 10.AH.223.158; 10.AH.223.196;10.AH.223.223; 10.AH.223.240; 10.AH.223.244; 10.AH.223.243;10.AH.223.247; 10.AH.240.157; 10.AH.240.158; 10.AH.240.196;10.AH.240.223; 10.AH.240.240; 10.AH.240.244; 10.AH.240.243;10.AH.240.247; 10.AH.244.157; 10.AH.244.158; 10.AH.244.196;10.AH.244.223; 10.AH.244.240; 10.AH.244.244; 10.AH.244.243;10.AH.244.247; 10.AH.247.157; 10.AH.247.158; 10.AH.247.196;10.AH.247.223; 10.AH.247.240; 10.AH.247.244; 10.AH.247.243;10.AH.247.247; Prodrugs of 10.AJ 10.AJ.4.157; 10.AJ.4.158; 10.AJ.4.196;10.AJ.4.223; 10.AJ.4.240; 10.AJ.4.244; 10.AJ.4.243; 10.AJ.4.247;10.AJ.5.157; 10.AJ.5.158; 10.AJ.5.196; 10.AJ.5.223; 10.AJ.5.240;10.AJ.5.244; 10.AJ.5.243; 10.AJ.5.247; 10.AJ.7.157; 10.AJ.7.158;10.AJ.7.196; 10.AJ.7.223; 10.AJ.7.240; 10.AJ.7.244; 10.AJ.7.243;10.AJ.7.247; 10.AJ.15.157; 10.AJ.15.158; 10.AJ.15.196; 10.AJ.15.223;10.AJ.15.240; 10.AJ.15.244; 10.AJ.15.243; 10.AJ.15.247; 10.AJ.16.157;10.AJ.16.158; 10.AJ.16.196; 10.AJ.16.223; 10.AJ.16.240; 10.AJ.16.244;10.AJ.16.243; 10.AJ.16.247; 10.AJ.18.157; 10.AJ.18.158; 10.AJ.18.196;10.AJ.18.223; 10.AJ.18.240; 10.AJ.18.244; 10.AJ.18.243; 10.AJ.18.247;10.AJ.26.157; 10.AJ.26.158; 10.AJ.26.196; 10.AJ.26.223; 10.AJ.26.240;10.AJ.26.244; 10.AJ.26.243; 10.AJ.26.247; 10.AJ.27.157; 10.AJ.27.158;10.AJ.27.196; 10.AJ.27.223; 10.AJ.27.240; 10.AJ.27.244; 10.AJ.27.243;10.AJ.27.247; 10.AJ.29.157; 10.AJ.29.158; 10.AJ.29.196; 10.AJ.29.223;10.AJ.29.240; 10.AJ.29.244; 10.AJ.29.243; 10.AJ.29.247; 10.AJ.54.157;10.AJ.54.158; 10.AJ.54.196; 10.AJ.54.223; 10.AJ.54.240; 10.AJ.54.244;10.AJ.54.243; 10.AJ.54.247; 10.AJ.55.157; 10.AJ.55.158; 10.AJ.55.196;10.AJ.55.223; 10.AJ.55.240; 10.AJ.55.244; 10.AJ.55.243; 10.AJ.55.247;10.AJ.56.157; 10.AJ.56.158; 10.AJ.56.196; 10.AJ.56.223; 10.AJ.56.240;10.AJ.56.244; 10.AJ.56.243; 10.AJ.56.247; 10.AJ.157.157; 10.AJ.157.158;10.AJ.157.196; 10.AJ.157.223; 10.AJ.157.240; 10.AJ.157.244;10.AJ.157.243; 10.AJ.157.247; 10.AJ.196.157; 10.AJ.196.158;10.AJ.196.196; 10.AJ.196.223; 10.AJ.196.240; 10.AJ.196.244;10.AJ.196.243; 10.AJ.196.247; 10.AJ.223.157; 10.AJ.223.158;10.AJ.223.196; 10.AJ.223.223; 10.AJ.223.240; 10.AJ.223.244;10.AJ.223.243; 10.AJ.223.247; 10.AJ.240.157; 10.AJ.240.158;10.AJ.240.196; 10.AJ.240.223; 10.AJ.240.240; 10.AJ.240.244;10.AJ.240.243; 10.AJ.240.247; 10.AJ.244.157; 10.AJ.244.158;10.AJ.244.196; 10.AJ.244.223; 10.AJ.244.240; 10.AJ.244.244;10.AJ.244.243; 10.AJ.244.247; 10.AJ.247.157; 10.AJ.247.158;10.AJ.247.196; 10.AJ.247.223; 10.AJ.247.240; 10.AJ.247.244;10.AJ.247.243; 10.AJ.247.247; Prodrugs of 10.AN 10.AN.4.157;10.AN.4.158; 10.AN.4.196; 10.AN.4.223; 10.AN.4.240; 10.AN.4.244;10.AN.4.243; 10.AN.4.247; 10.AN.5.157; 10.AN.5.158; 10.AN.5.196;10.AN.5.223; 10.AN.5.240; 10.AN.5.244; 10.AN.5.243; 10.AN.5.247;10.AN.7.157; 10.AN.7.158; 10.AN.7.196; 10.AN.7.223; 10.AN.7.240;10.AN.7.244; 10.AN.7.243; 10.AN.7.247; 10.AN.15.157; 10.AN.15.158;10.AN.15.196; 10.AN.15.223; 10.AN.15.240; 10.AN.15.244; 10.AN.15.243;10.AN.15.247; 10.AN.16.157; 10.AN.16.158; 10.AN.16.196; 10.AN.16.223;10.AN.16.240; 10.AN.16.244; 10.AN.16.243; 10.AN.16.247; 10.AN.18.157;10.AN.18.158; 10.AN.18.196; 10.AN.18.223; 10.AN.18.240; 10.AN.18.244;10.AN.18.243; 10.AN.18.247; 10.AN.26.157; 10.AN.26.158; 10.AN.26.196;10.AN.26.223; 10.AN.26.240; 10.AN.26.244; 10.AN.26.243; 10.AN.26.247;10.AN.27.157; 10.AN.27.158; 10.AN.27.196; 10.AN.27.223; 10.AN.27.240;10.AN.27.244; 10.AN.27.243; 10.AN.27.247; 10.AN.29.157; 10.AN.29.158;10.AN.29.196; 10.AN.29.223; 10.AN.29.240; 10.AN.29.244; 10.AN.29.243;10.AN.29.247; 10.AN.54.157; 10.AN.54.158; 10.AN.54.196; 10.AN.54.223;10.AN.54.240; 10.AN.54.244; 10.AN.54.243; 10.AN.54.247; 10.AN.55.157;10.AN.55.158; 10.AN.55.196; 10.AN.55.223; 10.AN.55.240; 10.AN.55.244;10.AN.55.243; 10.AN.55.247; 10.AN.56.157; 10.AN.56.158; 10.AN.56.196;10.AN.56.223; 10.AN.56.240; 10.AN.56.244; 10.AN.56.243; 10.AN.56.247;10.AN.157.157; 10.AN.157.158; 10.AN.157.196; 10.AN.157.223;10.AN.157.240; 10.AN.157.244; 10.AN.157.243; 10.AN.157.247;10.AN.196.157; 10.AN.196.158; 10.AN.196.196; 10.AN.196.223;10.AN.196.240; 10.AN.196.244; 10.AN.196.243; 10.AN.196.247;10.AN.223.157; 10.AN.223.158; 10.AN.223.196; 10.AN.223.223;10.AN.223.240; 10.AN.223.244; 10.AN.223.243; 10.AN.223.247;10.AN.240.157; 10.AN.240.158; 10.AN.240.196; 10.AN.240.223;10.AN.240.240; 10.AN.240.244; 10.AN.240.243; 10.AN.240.247;10.AN.244.157; 10.AN.244.158; 10.AN.244.196; 10.AN.244.223;10.AN.244.240; 10.AN.244.244; 10.AN.244.243; 10.AN.244.247;10.AN.247.157; 10.AN.247.158; 10.AN.247.196; 10.AN.247.223;10.AN.247.240; 10.AN.247.244; 10.AN.247.243; 10.AN.247.247; Prodrugs of10.AP 10.AP.4.157; 10.AP.4.158; 10.AP.4.196; 10.AP.4.223; 10.AP.4.240;10.AP.4.244; 10.AP.4.243; 10.AP.4.247; 10.AP.5.157; 10.AP.5.158;10.AP.5.196; 10.AP.5.223; 10.AP.5.240; 10.AP.5.244; 10.AP.5.243;10.AP.5.247; 10.AP.7.157; 10.AP.7.158; 10.AP.7.196; 10.AP.7.223;10.AP.7.240; 10.AP.7.244; 10.AP.7.243; 10.AP.7.247; 10.AP.15.157;10.AP.15.158; 10.AP.15.196; 10.AP.15.223; 10.AP.15.240; 10.AP.15.244;10.AP.15.243; 10.AP.15.247; 10.AP.16.157; 10.AP.16.158; 10.AP.16.196;10.AP.16.223; 10.AP.16.240; 10.AP.16.244; 10.AP.16.243; 10.AP.16.247;10.AP.18.157; 10.AP.18.158; 10.AP.18.196; 10.AP.18.223; 10.AP.18.240;10.AP.18.244; 10.AP.18.243; 10.AP.18.247; 10.AP.26.157; 10.AP.26.158;10.AP.26.196; 10.AP.26.223; 10.AP.26.240; 10.AP.26.244; 10.AP.26.243;10.AP.26.247; 10.AP.27.157; 10.AP.27.158; 10.AP.27.196; 10.AP.27.223;10.AP.27.240; 10.AP.27.244; 10.AP.27.243; 10.AP.27.247; 10.AP.29.157;10.AP.29.158; 10.AP.29.196; 10.AP.29.223; 10.AP.29.240; 10.AP.29.244;10.AP.29.243; 10.AP.29.247; 10.AP.54.157; 10.AP.54.158; 10.AP.54.196;10.AP.54.223; 10.AP.54.240; 10.AP.54.244; 10.AP.54.243; 10.AP.54.247;10.AP.55.157; 10.AP.55.158; 10.AP.55.196; 10.AP.55.223; 10.AP.55.240;10.AP.55.244; 10.AP.55.243; 10.AP.55.247; 10.AP.56.157; 10.AP.56.158;10.AP.56.196; 10.AP.56.223; 10.AP.56.240; 10.AP.56.244; 10.AP.56.243;10.AP.56.247; 10.AP.157.157; 10.AP.157.158; 10.AP.157.196;10.AP.157.223; 10.AP.157.240; 10.AP.157.244; 10.AP.157.243;10.AP.157.247; 10.AP.196.157; 10.AP.196.158; 10.AP.196.196;10.AP.196.223; 10.AP.196.240; 10.AP.196.244; 10.AP.196.243;10.AP.196.247; 10.AP.223.157; 10.AP.223.158; 10.AP.223.196;10.AP.223.223; 10.AP.223.240; 10.AP.223.244; 10.AP.223.243;10.AP.223.247; 10.AP.240.157; 10.AP.240.158; 10.AP.240.196;10.AP.240.223; 10.AP.240.240; 10.AP.240.244; 10.AP.240.243;10.AP.240.247; 10.AP.244.157; 10.AP.244.158; 10.AP.244.196;10.AP.244.223; 10.AP.244.240; 10.AP.244.244; 10.AP.244.243;10.AP.244.247; 10.AP.247.157; 10.AP.247.158; 10.AP.247.196;10.AP.247.223; 10.AP.247.240; 10.AP.247.244; 10.AP.247.243;10.AP.247.247; Prodrugs of 10.AZ 10.AZ.4.157; 10.AZ.4.158; 10.AZ.4.196;10.AZ.4.223; 10.AZ.4.240; 10.AZ.4.244; 10.AZ.4.243; 10.AZ.4.247;10.AZ.5.157; 10.AZ.5.158; 10.AZ.5.196; 10.AZ.5.223; 10.AZ.5.240;10.AZ.5.244; 10.AZ.5.243; 10.AZ.5.247; 10.AZ.7.157; 10.AZ.7.158;10.AZ.7.196; 10.AZ.7.223; 10.AZ.7.240; 10.AZ.7.244; 10.AZ.7.243;10.AZ.7.247; 10.AZ.15.157; 10.AZ.15.158; 10.AZ.15.196; 10.AZ.15.223;10.AZ.15.240; 10.AZ.15.244; 10.AZ.15.243; 10.AZ.15.247; 10.AZ.16.157;10.AZ.16.158; 10.AZ.16.196; 10.AZ.16.223; 10.AZ.16.240; 10.AZ.16.244;10.AZ.16.243; 10.AZ.16.247; 10.AZ.18.157; 10.AZ.18.158; 10.AZ.18.196;10.AZ.18.223; 10.AZ.18.240; 10.AZ.18.244; 10.AZ.18.243; 10.AZ.18.247;10.AZ.26.157; 10.AZ.26.158; 10.AZ.26.196; 10.AZ.26.223; 10.AZ.26.240;10.AZ.26.244; 10.AZ.26.243; 10.AZ.26.247; 10.AZ.27.157; 10.AZ.27.158;10.AZ.27.196; 10.AZ.27.223; 10.AZ.27.240; 10.AZ.27.244; 10.AZ.27.243;10.AZ.27.247; 10.AZ.29.157; 10.AZ.29.158; 10.AZ.29.196; 10.AZ.29.223;10.AZ.29.240; 10.AZ.29.244; 10.AZ.29.243; 10.AZ.29.247; 10.AZ.54.157;10.AZ.54.158; 10.AZ.54.196; 10.AZ.54.223; 10.AZ.54.240; 10.AZ.54.244;10.AZ.54.243; 10.AZ.54.247; 10.AZ.55.157; 10.AZ.55.158; 10.AZ.55.196;10.AZ.55.223; 10.AZ.55.240; 10.AZ.55.244; 10.AZ.55.243; 10.AZ.55.247;10.AZ.56.157; 10.AZ.56.158; 10.AZ.56.196; 10.AZ.56.223; 10.AZ.56.240;10.AZ.56.244; 10.AZ.56.243; 10.AZ.56.247; 10.AZ.157.157; 10.AZ.157.158;10.AZ.157.196; 10.AZ.157.223; 10.AZ.157.240; 10.AZ.157.244;10.AZ.157.243; 10.AZ.157.247; 10.AZ.196.157; 10.AZ.196.158;10.AZ.196.196; 10.AZ.196.223; 10.AZ.196.240; 10.AZ.196.244;10.AZ.196.243; 10.AZ.196.247; 10.AZ.223.157; 10.AZ.223.158;10.AZ.223.196; 10.AZ.223.223; 10.AZ.223.240; 10.AZ.223.244;10.AZ.223.243; 10.AZ.223.247; 10.AZ.240.157; 10.AZ.240.158;10.AZ.240.196; 10.AZ.240.223; 10.AZ.240.240; 10.AZ.240.244;10.AZ.240.243; 10.AZ.240.247; 10.AZ.244.157; 10.AZ.244.158;10.AZ.244.196; 10.AZ.244.223; 10.AZ.244.240; 10.AZ.244.244;10.AZ.244.243; 10.AZ.244.247; 10.AZ.247.157; 10.AZ.247.158;10.AZ.247.196; 10.AZ.247.223; 10.AZ.247.240; 10.AZ.247.244;10.AZ.247.243; 10.AZ.247.247; Prodrugs of 10.BF 10.BF.4.157;10.BF.4.158; 10.BF.4.196; 10.BF.4.223; 10.BF.4.240; 10.BF.4.244;10.BF.4.243; 10.BF.4.247; 10.BF.5.157; 10.BF.5.158; 10.BF.5.196;10.BF.5.223; 10.BF.5.240; 10.BF.5.244; 10.BF.5.243; 10.BF.5.247;10.BF.7.157; 10.BF.7.158; 10.BF.7.196; 10.BF.7.223; 10.BF.7.240;10.BF.7.244; 10.BF.7.243; 10.BF.7.247; 10.BF.15.157; 10.BF.15.158;10.BF.15.196; 10.BF.15.223; 10.BF.15.240; 10.BF.15.244; 10.BF.15.243;10.BF.15.247; 10.BF.16.157; 10.BF.16.158; 10.BF.16.196; 10.BF.16.223;10.BF.16.240; 10.BF.16.244; 10.BF.16.243; 10.BF.16.247; 10.BF.18.157;10.BF.18.158; 10.BF.18.196; 10.BF.18.223; 10.BF.18.240; 10.BF.18.244;10.BF.18.243; 10.BF.18.247; 10.BF.26.157; 10.BF.26.158; 10.BF.26.196;10.BF.26.223; 10.BF.26.240; 10.BF.26.244; 10.BF.26.243; 10.BF.26.247;10.BF.27.157; 10.BF.27.158; 10.BF.27.196; 10.BF.27.223; 10.BF.27.240;10.BF.27.244; 10.BF.27.243; 10.BF.27.247; 10.BF.29.157; 10.BF.29.158;10.BF.29.196; 10.BF.29.223; 10.BF.29.240; 10.BF.29.244; 10.BF.29.243;10.BF.29.247; 10.BF.54.157; 10.BF.54.158; 10.BF.54.196; 10.BF.54.223;10.BF.54.240; 10.BF.54.244; 10.BF.54.243; 10.BF.54.247; 10.BF.55.157;10.BF.55.158; 10.BF.55.196; 10.BF.55.223; 10.BF.55.240; 10.BF.55.244;10.BF.55.243; 10.BF.55.247; 10.BF.56.157; 10.BF.56.158; 10.BF.56.196;10.BF.56.223; 10.BF.56.240; 10.BF.56.244; 10.BF.56.243; 10.BF.56.247;10.BF.157.157; 10.BF.157.158; 10.BF.157.196; 10.BF.157.223;10.BF.157.240; 10.BF.157.244; 10.BF.157.243; 10.BF.157.247;10.BF.196.157; 10.BF.196.158; 10.BF.196.196; 10.BF.196.223;10.BF.196.240; 10.BF.196.244; 10.BF.196.243; 10.BF.196.247;10.BF.223.157; 10.BF.223.158; 10.BF.223.196; 10.BF.223.223;10.BF.223.240; 10.BF.223.244; 10.BF.223.243; 10.BF.223.247;10.BF.240.157; 10.BF.240.158; 10.BF.240.196; 10.BF.240.223;10.BF.240.240; 10.BF.240.244; 10.BF.240.243; 10.BF.240.247;10.BF.244.157; 10.BF.244.158; 10.BF.244.196; 10.BF.244.223;10.BF.244.240; 10.BF.244.244; 10.BF.244.243; 10.BF.244.247;10.BF.247.157; 10.BF.247.158; 10.BF.247.196; 10.BF.247.223;10.BF.247.240; 10.BF.247.244; 10.BF.247.243; 10.BF.247.247; Prodrugs of10.CI 10.CI.4.157; 10.CI.4.158; 10.CI.4.196; 10.CI.4.223; 10.CI.4.240;10.CI.4.244; 10.CI.4.243; 10.CI.4.247; 10.CI.5.157; 10.CI.5.158;10.CI.5.196; 10.CI.5.223; 10.CI.5.240; 10.CI.5.244; 10.CI.5.243;10.CI.5.247; 10.CI.7.157; 10.CI.7.158; 10.CI.7.196; 10.CI.7.223;10.CI.7.240; 10.CI.7.244; 10.CI.7.243; 10.CI.7.247; 10.CI.15.157;10.CI.15.158; 10.CI.15.196; 10.CI.15.223; 10.CI.15.240; 10.CI.15.244;10.CI.15.243; 10.CI.15.247; 10.CI.16.157; 10.CI.16.158; 10.CI.16.196;10.CI.16.223; 10.CI.16.240; 10.CI.16.244; 10.CI.16.243; 10.CI.16.247;10.CI.18.157; 10.CI.18.158; 10.CI.18.196; 10.CI.18.223; 10.CI.18.240;10.CI.18.244; 10.CI.18.243; 10.CI.18.247; 10.CI.26.157; 10.CI.26.158;10.CI.26.196; 10.CI.26.223; 10.CI.26.240; 10.CI.26.244; 10.CI.26.243;10.CI.26.247; 10.CI.27.157; 10.CI.27.158; 10.CI.27.196; 10.CI.27.223;10.CI.27.240; 10.CI.27.244; 10.CI.27.243; 10.CI.27.247; 10.CI.29.157;10.CI.29.158; 10.CI.29.196; 10.CI.29.223; 10.CI.29.240; 10.CI.29.244;10.CI.29.243; 10.CI.29.247; 10.CI.54.157; 10.CI.54.158; 10.CI.54.196;10.CI.54.223; 10.CI.54.240; 10.CI.54.244; 10.CI.54.243; 10.CI.54.247;10.CI.55.157; 10.CI.55.158; 10.CI.55.196; 10.CI.55.223; 10.CI.55.240;10.CI.55.244; 10.CI.55.243; 10.CI.55.247; 10.CI.56.157; 10.CI.56.158;10.CI.56.196; 10.CI.56.223; 10.CI.56.240; 10.CI.56.244; 10.CI.56.243;10.CI.56.247; 10.CI.157.157; 10.CI.157.158; 10.CI.157.196;10.CI.157.223; 10.CI.157.240; 10.CI.157.244; 10.CI.157.243;10.CI.157.247; 10.CI.196.157; 10.CI.196.158; 10.CI.196.196;10.CI.196.223; 10.CI.196.240; 10.CI.196.244; 10.CI.196.243;10.CI.196.247; 10.CI.223.157; 10.CI.223.158; 10.CI.223.196;10.CI.223.223; 10.CI.223.240; 10.CI.223.244; 10.CI.223.243;10.CI.223.247; 10.CI.240.157; 10.CI.240.158; 10.CI.240.196;10.CI.240.223; 10.CI.240.240; 10.CI.240.244; 10.CI.240.243;10.CI.240.247; 10.CI.244.157; 10.CI.244.158; 10.CI.244.196;10.CI.244.223; 10.CI.244.240; 10.CI.244.244; 10.CI.244.243;10.CI.244.247; 10.CI.247.157; 10.CI.247.158; 10.CI.247.196;10.CI.247.223; 10.CI.247.240; 10.CI.247.244; 10.CI.247.243;10.CI.247.247; Prodrugs of 10.CO 10.CO.4.157; 10.CO.4.158; 10.CO.4.196;10.CO.4.223; 10.CO.4.240; 10.CO.4.244; 10.CO.4.243; 10.CO.4.247;10.CO.5.157; 10.CO.5.158; 10.CO.5.196; 10.CO.5.223; 10.CO.5.240;10.CO.5.244; 10.CO.5.243; 10.CO.5.247; 10.CO.7.157; 10.CO.7.158;10.CO.7.196; 10.CO.7.223; 10.CO.7.240; 10.CO.7.244; 10.CO.7.243;10.CO.7.247; 10.CO.15.157; 10.CO.15.158; 10.CO.15.196; 10.CO.15.223;10.CO.15.240; 10.CO.15.244; 10.CO.15.243; 10.CO.15.247; 10.CO.16.157;10.CO.16.158; 10.CO.16.196; 10.CO.16.223; 10.CO.16.240; 10.CO.16.244;10.CO.16.243; 10.CO.16.247; 10.CO.18.157; 10.CO.18.158; 10.CO.18.196;10.CO.18.223; 10.CO.18.240; 10.CO.18.244; 10.CO.18.243; 10.CO.18.247;10.CO.26.157; 10.CO.26.158; 10.CO.26.196; 10.CO.26.223; 10.CO.26.240;10.CO.26.244; 10.CO.26.243; 10.CO.26.247; 10.CO.27.157; 10.CO.27.158;10.CO.27.196; 10.CO.27.223; 10.CO.27.240; 10.CO.27.244; 10.CO.27.243;10.CO.27.247; 10.CO.29.157; 10.CO.29.158; 10.CO.29.196; 10.CO.29.223;10.CO.29.240; 10.CO.29.244; 10.CO.29.243; 10.CO.29.247; 10.CO.54.157;10.CO.54.158; 10.CO.54.196; 10.CO.54.223; 10.CO.54.240; 10.CO.54.244;10.CO.54.243; 10.CO.54.247; 10.CO.55.157; 10.CO.55.158; 10.CO.55.196;10.CO.55.223; 10.CO.55.240; 10.CO.55.244; 10.CO.55.243; 10.CO.55.247;10.CO.56.157; 10.CO.56.158; 10.CO.56.196; 10.CO.56.223; 10.CO.56.240;10.CO.56.244; 10.CO.56.243; 10.CO.56.247; 10.CO.157.157; 10.CO.157.158;10.CO.157.196; 10.CO.157.223; 10.CO.157.240; 10.CO.157.244;10.CO.157.243; 10.CO.157.247; 10.CO.196.157; 10.CO.196.158;10.CO.196.196; 10.CO.196.223; 10.CO.196.240; 10.CO.196.244;10.CO.196.243; 10.CO.196.247; 10.CO.223.157; 10.CO.223.158;10.CO.223.196; 10.CO.223.223; 10.CO.223.240; 10.CO.223.244;10.CO.223.243; 10.CO.223.247; 10.CO.240.157; 10.CO.240.158;10.CO.240.196; 10.CO.240.223; 10.CO.240.240; 10.CO.240.244;10.CO.240.243; 10.CO.240.247; 10.CO.244.157; 10.CO.244.158;10.CO.244.196; 10.CO.244.223; 10.CO.244.240; 10.CO.244.244;10.CO.244.243; 10.CO.244.247; 10.CO.247.157; 10.CO.247.158;10.CO.247.196; 10.CO.247.223; 10.CO.247.240; 10.CO.247.244;10.CO.247.243; 10.CO.247.247; Prodrugs of 11.AH 11.AH.4.157;11.AH.4.158; 11.AH.4.196; 11.AH.4.223; 11.AH.4.240; 11.AH.4.244;11.AH.4.243; 11.AH.4.247; 11.AH.5.157; 11.AH.5.158; 11.AH.5.196;11.AH.5.223; 11.AH.5.240; 11.AH.5.244; 11.AH.5.243; 11.AH.5.247;11.AH.7.157; 11.AH.7.158; 11.AH.7.196; 11.AH.7.223; 11.AH.7.240;11.AH.7.244; 11.AH.7.243; 11.AH.7.247; 11.AH.15.157; 11.AH.15.158;11.AH.15.196; 11.AH.15.223; 11.AH.15.240; 11.AH.15.244; 11.AH.15.243;11.AH.15.247; 11.AH.16.157; 11.AH.16.158; 11.AH.16.196; 11.AH.16.223;11.AH.16.240; 11.AH.16.244; 11.AH.16.243; 11.AH.16.247; 11.AH.18.157;11.AH.18.158; 11.AH.18.196; 11.AH.18.223; 11.AH.18.240; 11.AH.18.244;11.AH.18.243; 11.AH.18.247; 11.AH.26.157; 11.AH.26.158; 11.AH.26.196;11.AH.26.223; 11.AH.26.240; 11.AH.26.244; 11.AH.26.243; 11.AH.26.247;11.AH.27.157; 11.AH.27.158; 11.AH.27.196; 11.AH.27.223; 11.AH.27.240;11.AH.27.244; 11.AH.27.243; 11.AH.27.247; 11.AH.29.157; 11.AH.29.158;11.AH.29.196; 11.AH.29.223; 11.AH.29.240; 11.AH.29.244; 11.AH.29.243;11.AH.29.247; 11.AH.54.157; 11.AH.54.158; 11.AH.54.196; 11.AH.54.223;11.AH.54.240; 11.AH.54.244; 11.AH.54.243; 11.AH.54.247; 11.AH.55.157;11.AH.55.158; 11.AH.55.196; 11.AH.55.223; 11.AH.55.240; 11.AH.55.244;11.AH.55.243; 11.AH.55.247; 11.AH.56.157; 11.AH.56.158; 11.AH.56.196;11.AH.56.223; 11.AH.56.240; 11.AH.56.244; 11.AH.56.243; 11.AH.56.247;11.AH.157.157; 11.AH.157.158; 11.AH.157.196; 11.AH.157.223;11.AH.157.240; 11.AH.157.244; 11.AH.157.243; 11.AH.157.247;11.AH.196.157; 11.AH.196.158; 11.AH.196.196; 11.AH.196.223;11.AH.196.240; 11.AH.196.244; 11.AH.196.243; 11.AH.196.247;11.AH.223.157; 11.AH.223.158; 11.AH.223.196; 11.AH.223.223;11.AH.223.240; 11.AH.223.244; 11.AH.223.243; 11.AH.223.247;11.AH.240.157; 11.AH.240.158; 11.AH.240.196; 11.AH.240.223;11.AH.240.240; 11.AH.240.244; 11.AH.240.243; 11.AH.240.247;11.AH.244.157; 11.AH.244.158; 11.AH.244.196; 11.AH.244.223;11.AH.244.240; 11.AH.244.244; 11.AH.244.243; 11.AH.244.247;11.AH.247.157; 11.AH.247.158; 11.AH.247.196; 11.AH.247.223;11.AH.247.240; 11.AH.247.244; 11.AH.247.243; 11.AH.247.247; Prodrugs of11.AJ 11.AJ.4.157; 11.AJ.4.158; 11.AJ.4.196; 11.AJ.4.223; 11.AJ.4.240;11.AJ.4.244; 11.AJ.4.243; 11.AJ.4.247; 11.AJ.5.157; 11.AJ.5.158;11.AJ.5.196; 11.AJ.5.223; 11.AJ.5.240; 11.AJ.5.244; 11.AJ.5.243;11.AJ.5.247; 11.AJ.7.157; 11.AJ.7.158; 11.AJ.7.196; 11.AJ.7.223;11.AJ.7.240; 11.AJ.7.244; 11.AJ.7.243; 11.AJ.7.247; 11.AJ.15.157;11.AJ.15.158; 11.AJ.15.196; 11.AJ.15.223; 11.AJ.15.240; 11.AJ.15.244;11.AJ.15.243; 11.AJ.15.247; 11.AJ.16.157; 11.AJ.16.158; 11.AJ.16.196;11.AJ.16.223; 11.AJ.16.240; 11.AJ.16.244; 11.AJ.16.243; 11.AJ.16.247;11.AJ.18.157; 11.AJ.18.158; 11.AJ.18.196; 11.AJ.18.223; 11.AJ.18.240;11.AJ.18.244; 11.AJ.18.243; 11.AJ.18.247; 11.AJ.26.157; 11.AJ.26.158;11.AJ.26.196; 11.AJ.26.223; 11.AJ.26.240; 11.AJ.26.244; 11.AJ.26.243;11.AJ.26.247; 11.AJ.27.157; 11.AJ.27.158; 11.AJ.27.196; 11.AJ.27.223;11.AJ.27.240; 11.AJ.27.244; 11.AJ.27.243; 11.AJ.27.247; 11.AJ.29.157;11.AJ.29.158; 11.AJ.29.196; 11.AJ.29.223; 11.AJ.29.240; 11.AJ.29.244;11.AJ.29.243; 11.AJ.29.247; 11.AJ.54.157; 11.AJ.54.158; 11.AJ.54.196;11.AJ.54.223; 11.AJ.54.240; 11.AJ.54.244; 11.AJ.54.243; 11.AJ.54.247;11.AJ.55.157; 11.AJ.55.158; 11.AJ.55.196; 11.AJ.55.223; 11.AJ.55.240;11.AJ.55.244; 11.AJ.55.243; 11.AJ.55.247; 11.AJ.56.157; 11.AJ.56.158;11.AJ.56.196; 11.AJ.56.223; 11.AJ.56.240; 11.AJ.56.244; 11.AJ.56.243;11.AJ.56.247; 11.AJ.157.157; 11.AJ.157.158; 11.AJ.157.196;11.AJ.157.223; 11.AJ.157.240; 11.AJ.157.244; 11.AJ.157.243;11.AJ.157.247; 11.AJ.196.157; 11.AJ.196.158; 11.AJ.196.196;11.AJ.196.223; 11.AJ.196.240; 11.AJ.196.244; 11.AJ.196.243;11.AJ.196.247; 11.AJ.223.157; 11.AJ.223.158; 11.AJ.223.196;11.AJ.223.223; 11.AJ.223.240; 11.AJ.223.244; 11.AJ.223.243;11.AJ.223.247; 11.AJ.240.157; 11.AJ.240.158; 11.AJ.240.196;11.AJ.240.223; 11.AJ.240.240; 11.AJ.240.244; 11.AJ.240.243;11.AJ.240.247; 11.AJ.244.157; 11.AJ.244.158; 11.AJ.244.196;11.AJ.244.223; 11.AJ.244.240; 11.AJ.244.244; 11.AJ.244.243;11.AJ.244.247; 11.AJ.247.157; 11.AJ.247.158; 11.AJ.247.196;11.AJ.247.223; 11.AJ.247.240; 11.AJ.247.244; 11.AJ.247.243;11.AJ.247.247; Prodrugs of 11.AN 11.AN.4.157; 11.AN.4.158; 11.AN.4.196;11.AN.4.223; 11.AN.4.240; 11.AN.4.244; 11.AN.4.243; 11.AN.4.247;11.AN.5.157; 11.AN.5.158; 11.AN.5.196; 11.AN.5.223; 11.AN.5.240;11.AN.5.244; 11.AN.5.243; 11.AN.5.247; 11.AN.7.157; 11.AN.7.158;11.AN.7.196; 11.AN.7.223; 11.AN.7.240; 11.AN.7.244; 11.AN.7.243;11.AN.7.247; 11.AN.15.157; 11.AN.15.158; 11.AN.15.196; 11.AN.15.223;11.AN.15.240; 11.AN.15.244; 11.AN.15.243; 11.AN.15.247; 11.AN.16.157;11.AN.16.158; 11.AN.16.196; 11.AN.16.223; 11.AN.16.240; 11.AN.16.244;11.AN.16.243; 11.AN.16.247; 11.AN.18.157; 11.AN.18.158; 11.AN.18.196;11.AN.18.223; 11.AN.18.240; 11.AN.18.244; 11.AN.18.243; 11.AN.18.247;11.AN.26.157; 11.AN.26.158; 11.AN.26.196; 11.AN.26.223; 11.AN.26.240;11.AN.26.244; 11.AN.26.243; 11.AN.26.247; 11.AN.27.157; 11.AN.27.158;11.AN.27.196; 11.AN.27.223; 11.AN.27.240; 11.AN.27.244; 11.AN.27.243;11.AN.27.247; 11.AN.29.157; 11.AN.29.158; 11.AN.29.196; 11.AN.29.223;11.AN.29.240; 11.AN.29.244; 11.AN.29.243; 11.AN.29.247; 11.AN.54.157;11.AN.54.158; 11.AN.54.196; 11.AN.54.223; 11.AN.54.240; 11.AN.54.244;11.AN.54.243; 11.AN.54.247; 11.AN.55.157; 11.AN.55.158; 11.AN.55.196;11.AN.55.223; 11.AN.55.240; 11.AN.55.244; 11.AN.55.243; 11.AN.55.247;11.AN.56.157; 11.AN.56.158; 11.AN.56.196; 11.AN.56.223; 11.AN.56.240;11.AN.56.244; 11.AN.56.243; 11.AN.56.247; 11.AN.157.157; 11.AN.157.158;11.AN.157.196; 11.AN.157.223; 11.AN.157.240; 11.AN.157.244;11.AN.157.243; 11.AN.157.247; 11.AN.196.157; 11.AN.196.158;11.AN.196.196; 11.AN.196.223; 11.AN.196.240; 11.AN.196.244;11.AN.196.243; 11.AN.196.247; 11.AN.223.157; 11.AN.223.158;11.AN.223.196; 11.AN.223.223; 11.AN.223.240; 11.AN.223.244;11.AN.223.243; 11.AN.223.247; 11.AN.240.157; 11.AN.240.158;11.AN.240.196; 11.AN.240.223; 11.AN.240.240; 11.AN.240.244;11.AN.240.243; 11.AN.240.247; 11.AN.244.157; 11.AN.244.158;11.AN.244.196; 11.AN.244.223; 11.AN.244.240; 11.AN.244.244;11.AN.244.243; 11.AN.244.247; 11.AN.247.157; 11.AN.247.158;11.AN.247.196; 11.AN.247.223; 11.AN.247.240; 11.AN.247.244;11.AN.247.243; 11.AN.247.247; Prodrugs of 11.AP 11.AP.4.157;11.AP.4.158; 11.AP.4.196; 11.AP.4.223; 11.AP.4.240; 11.AP.4.244;11.AP.4.243; 11.AP.4.247; 11.AP.5.157; 11.AP.5.158; 11.AP.5.196;11.AP.5.223; 11.AP.5.240; 11.AP.5.244; 11.AP.5.243; 11.AP.5.247;11.AP.7.157; 11.AP.7.158; 11.AP.7.196; 11.AP.7.223; 11.AP.7.240;11.AP.7.244; 11.AP.7.243; 11.AP.7.247; 11.AP.15.157; 11.AP.15.158;11.AP.15.196; 11.AP.15.223; 11.AP.15.240; 11.AP.15.244; 11.AP.15.243;11.AP.15.247; 11.AP.16.157; 11.AP.16.158; 11.AP.16.196; 11.AP.16.223;11.AP.16.240; 11.AP.16.244; 11.AP.16.243; 11.AP.16.247; 11.AP.18.157;11.AP.18.158; 11.AP.18.196; 11.AP.18.223; 11.AP.18.240; 11.AP.18.244;11.AP.18.243; 11.AP.18.247; 11.AP.26.157; 11.AP.26.158; 11.AP.26.196;11.AP.26.223; 11.AP.26.240; 11.AP.26.244; 11.AP.26.243; 11.AP.26.247;11.AP.27.157; 11.AP.27.158; 11.AP.27.196; 11.AP.27.223; 11.AP.27.240;11.AP.27.244; 11.AP.27.243; 11.AP.27.247; 11.AP.29.157; 11.AP.29.158;11.AP.29.196; 11.AP.29.223; 11.AP.29.240; 11.AP.29.244; 11.AP.29.243;11.AP.29.247; 11.AP.54.157; 11.AP.54.158; 11.AP.54.196; 11.AP.54.223;11.AP.54.240; 11.AP.54.244; 11.AP.54.243; 11.AP.54.247; 11.AP.55.157;11.AP.55.158; 11.AP.55.196; 11.AP.55.223; 11.AP.55.240; 11.AP.55.244;11.AP.55.243; 11.AP.55.247; 11.AP.56.157; 11.AP.56.158; 11.AP.56.196;11.AP.56.223; 11.AP.56.240; 11.AP.56.244; 11.AP.56.243; 11.AP.56.247;11.AP.157.157; 11.AP.157.158; 11.AP.157.196; 11.AP.157.223;11.AP.157.240; 11.AP.157.244; 11.AP.157.243; 11.AP.157.247;11.AP.196.157; 11.AP.196.158; 11.AP.196.196; 11.AP.196.223;11.AP.196.240; 11.AP.196.244; 11.AP.196.243; 11.AP.196.247;11.AP.223.157; 11.AP.223.158; 11.AP.223.196; 11.AP.223.223;11.AP.223.240; 11.AP.223.244; 11.AP.223.243; 11.AP.223.247;11.AP.240.157; 11.AP.240.158; 11.AP.240.196; 11.AP.240.223;11.AP.240.240; 11.AP.240.244; 11.AP.240.243; 11.AP.240.247;11.AP.244.157; 11.AP.244.158; 11.AP.244.196; 11.AP.244.223;11.AP.244.240; 11.AP.244.244; 11.AP.244.243; 11.AP.244.247;11.AP.247.157; 11.AP.247.158; 11.AP.247.196; 11.AP.247.223;11.AP.247.240; 11.AP.247.244; 11.AP.247.243; 11.AP.247.247; Prodrugs of11.AZ 11.AZ.4.157; 11.AZ.4.158; 11.AZ.4.196; 11.AZ.4.223; 11.AZ.4.240;11.AZ.4.244; 11.AZ.4.243; 11.AZ.4.247; 11.AZ.5.157; 11.AZ.5.158;11.AZ.5.196; 11.AZ.5.223; 11.AZ.5.240; 11.AZ.5.244; 11.AZ.5.243;11.AZ.5.247; 11.AZ.7.157; 11.AZ.7.158; 11.AZ.7.196; 11.AZ.7.223;11.AZ.7.240; 11.AZ.7.244; 11.AZ.7.243; 11.AZ.7.247; 11.AZ.15.157;11.AZ.15.158; 11.AZ.15.196; 11.AZ.15.223; 11.AZ.15.240; 11.AZ.15.244;11.AZ.15.243; 11.AZ.15.247; 11.AZ.16.157; 11.AZ.16.158; 11.AZ.16.196;11.AZ.16.223; 11.AZ.16.240; 11.AZ.16.244; 11.AZ.16.243; 11.AZ.16.247;11.AZ.18.157; 11.AZ.18.158; 11.AZ.18.196; 11.AZ.18.223; 11.AZ.18.240;11.AZ.18.244; 11.AZ.18.243; 11.AZ.18.247; 11.AZ.26.157; 11.AZ.26.158;11.AZ.26.196; 11.AZ.26.223; 11.AZ.26.240; 11.AZ.26.244; 11.AZ.26.243;11.AZ.26.247; 11.AZ.27.157; 11.AZ.27.158; 11.AZ.27.196; 11.AZ.27.223;11.AZ.27.240; 11.AZ.27.244; 11.AZ.27.243; 11.AZ.27.247; 11.AZ.29.157;11.AZ.29.158; 11.AZ.29.196; 11.AZ.29.223; 11.AZ.29.240; 11.AZ.29.244;11.AZ.29.243; 11.AZ.29.247; 11.AZ.54.157; 11.AZ.54.158; 11.AZ.54.196;11.AZ.54.223; 11.AZ.54.240; 11.AZ.54.244; 11.AZ.54.243; 11.AZ.54.247;11.AZ.55.157; 11.AZ.55.158; 11.AZ.55.196; 11.AZ.55.223; 11.AZ.55.240;11.AZ.55.244; 11.AZ.55.243; 11.AZ.55.247; 11.AZ.56.157; 11.AZ.56.158;11.AZ.56.196; 11.AZ.56.223; 11.AZ.56.240; 11.AZ.56.244; 11.AZ.56.243;11.AZ.56.247; 11.AZ.157.157; 11.AZ.157.158; 11.AZ.157.196;11.AZ.157.223; 11.AZ.157.240; 11.AZ.157.244; 11.AZ.157.243;11.AZ.157.247; 11.AZ.196.157; 11.AZ.196.158; 11.AZ.196.196;11.AZ.196.223; 11.AZ.196.240; 11.AZ.196.244; 11.AZ.196.243;11.AZ.196.247; 11.AZ.223.157; 11.AZ.223.158; 11.AZ.223.196;11.AZ.223.223; 11.AZ.223.240; 11.AZ.223.244; 11.AZ.223.243;11.AZ.223.247; 11.AZ.240.157; 11.AZ.240.158; 11.AZ.240.196;11.AZ.240.223; 11.AZ.240.240; 11.AZ.240.244; 11.AZ.240.243;11.AZ.240.247; 11.AZ.244.157; 11.AZ.244.158; 11.AZ.244.196;11.AZ.244.223; 11.AZ.244.240; 11.AZ.244.244; 11.AZ.244.243;11.AZ.244.247; 11.AZ.247.157; 11.AZ.247.158; 11.AZ.247.196;11.AZ.247.223; 11.AZ.247.240; 11.AZ.247.244; 11.AZ.247.243;11.AZ.247.247; Prodrugs of 11.BF 11.BF.4.157; 11.BF.4.158; 11.BF.4.196;11.BF.4.223; 11.BF.4.240; 11.BF.4.244; 11.BF.4.243; 11.BF.4.247;11.BF.5.157; 11.BF.5.158; 11.BF.5.196; 11.BF.5.223; 11.BF.5.240;11.BF.5.244; 11.BF.5.243; 11.BF.5.247; 11.BF.7.157; 11.BF.7.158;11.BF.7.196; 11.BF.7.223; 11.BF.7.240; 11.BF.7.244; 11.BF.7.243;11.BF.7.247; 11.BF.15.157; 11.BF.15.158; 11.BF.15.196; 11.BF.15.223;11.BF.15.240; 11.BF.15.244; 11.BF.15.243; 11.BF.15.247; 11.BF.16.157;11.BF.16.158; 11.BF.16.196; 11.BF.16.223; 11.BF.16.240; 11.BF.16.244;11.BF.16.243; 11.BF.16.247; 11.BF.18.157; 11.BF.18.158; 11.BF.18.196;11.BF.18.223; 11.BF.18.240; 11.BF.18.244; 11.BF.18.243; 11.BF.18.247;11.BF.26.157; 11.BF.26.158; 11.BF.26.196; 11.BF.26.223; 11.BF.26.240;11.BF.26.244; 11.BF.26.243; 11.BF.26.247; 11.BF.27.157; 11.BF.27.158;11.BF.27.196; 11.BF.27.223; 11.BF.27.240; 11.BF.27.244; 11.BF.27.243;11.BF.27.247; 11.BF.29.157; 11.BF.29.158; 11.BF.29.196; 11.BF.29.223;11.BF.29.240; 11.BF.29.244; 11.BF.29.243; 11.BF.29.247; 11.BF.54.157;11.BF.54.158; 11.BF.54.196; 11.BF.54.223; 11.BF.54.240; 11.BF.54.244;11.BF.54.243; 11.BF.54.247; 11.BF.55.157; 11.BF.55.158; 11.BF.55.196;11.BF.55.223; 11.BF.55.240; 11.BF.55.244; 11.BF.55.243; 11.BF.55.247;11.BF.56.157; 11.BF.56.158; 11.BF.56.196; 11.BF.56.223; 11.BF.56.240;11.BF.56.244; 11.BF.56.243; 11.BF.56.247; 11.BF.157.157; 11.BF.157.158;11.BF.157.196; 11.BF.157.223; 11.BF.157.240; 11.BF.157.244;11.BF.157.243; 11.BF.157.247; 11.BF.196.157; 11.BF.196.158;11.BF.196.196; 11.BF.196.223; 11.BF.196.240; 11.BF.196.244;11.BF.196.243; 11.BF.196.247; 11.BF.223.157; 11.BF.223.158;11.BF.223.196; 11.BF.223.223; 11.BF.223.240; 11.BF.223.244;11.BF.223.243; 11.BF.223.247; 11.BF.240.157; 11.BF.240.158;11.BF.240.196; 11.BF.240.223; 11.BF.240.240; 11.BF.240.244;11.BF.240.243; 11.BF.240.247; 11.BF.244.157; 11.BF.244.158;11.BF.244.196; 11.BF.244.223; 11.BF.244.240; 11.BF.244.244;11.BF.244.243; 11.BF.244.247; 11.BF.247.157; 11.BF.247.158;11.BF.247.196; 11.BF.247.223; 11.BF.247.240; 11.BF.247.244;11.BF.247.243; 11.BF.247.247; Prodrugs of 11.CI 11.CI.4.157;11.CI.4.158; 11.CI.4.196; 11.CI.4.223; 11.CI.4.240; 11.CI.4.244;11.CI.4.243; 11.CI.4.247; 11.CI.5.157; 11.CI.5.158; 11.CI.5.196;11.CI.5.223; 11.CI.5.240; 11.CI.5.244; 11.CI.5.243; 11.CI.5.247;11.CI.7.157; 11.CI.7.158; 11.CI.7.196; 11.CI.7.223; 11.CI.7.240;11.CI.7.244; 11.CI.7.243; 11.CI.7.247; 11.CI.15.157; 11.CI.15.158;11.CI.15.196; 11.CI.15.223; 11.CI.15.240; 11.CI.15.244; 11.CI.15.243;11.CI.15.247; 11.CI.16.157; 11.CI.16.158; 11.CI.16.196; 11.CI.16.223;11.CI.16.240; 11.CI.16.244; 11.CI.16.243; 11.CI.16.247; 11.CI.18.157;11.CI.18.158; 11.CI.18.196; 11.CI.18.223; 11.CI.18.240; 11.CI.18.244;11.CI.18.243; 11.CI.18.247; 11.CI.26.157; 11.CI.26.158; 11.CI.26.196;11.CI.26.223; 11.CI.26.240; 11.CI.26.244; 11.CI.26.243; 11.CI.26.247;11.CI.27.157; 11.CI.27.158; 11.CI.27.196; 11.CI.27.223; 11.CI.27.240;11.CI.27.244; 11.CI.27.243; 11.CI.27.247; 11.CI.29.157; 11.CI.29.158;11.CI.29.196; 11.CI.29.223; 11.CI.29.240; 11.CI.29.244; 11.CI.29.243;11.CI.29.247; 11.CI.54.157; 11.CI.54.158; 11.CI.54.196; 11.CI.54.223;11.CI.54.240; 11.CI.54.244; 11.CI.54.243; 11.CI.54.247; 11.CI.55.157;11.CI.55.158; 11.CI.55.196; 11.CI.55.223; 11.CI.55.240; 11.CI.55.244;11.CI.55.243; 11.CI.55.247; 11.CI.56.157; 11.CI.56.158; 11.CI.56.196;11.CI.56.223; 11.CI.56.240; 11.CI.56.244; 11.CI.56.243; 11.CI.56.247;11.CI.157.157; 11.CI.157.158; 11.CI.157.196; 11.CI.157.223;11.CI.157.240; 11.CI.157.244; 11.CI.157.243; 11.CI.157.247;11.CI.196.157; 11.CI.196.158; 11.CI.196.196; 11.CI.196.223;11.CI.196.240; 11.CI.196.244; 11.CI.196.243; 11.CI.196.247;11.CI.223.157; 11.CI.223.158; 11.CI.223.196; 11.CI.223.223;11.CI.223.240; 11.CI.223.244; 11.CI.223.243; 11.CI.223.247;11.CI.240.157; 11.CI.240.158; 11.CI.240.196; 11.CI.240.223;11.CI.240.240; 11.CI.240.244; 11.CI.240.243; 11.CI.240.247;11.CI.244.157; 11.CI.244.158; 11.CI.244.196; 11.CI.244.223;11.CI.244.240; 11.CI.244.244; 11.CI.244.243; 11.CI.244.247;11.CI.247.157; 11.CI.247.158; 11.CI.247.196; 11.CI.247.223;11.CI.247.240; 11.CI.247.244; 11.CI.247.243; 11.CI.247.247; Prodrugs of11.CO 11.CO.4.157; 11.CO.4.158; 11.CO.4.196; 11.CO.4.223; 11.CO.4.240;11.CO.4.244; 11.CO.4.243; 11.CO.4.247; 11.CO.5.157; 11.CO.5.158;11.CO.5.196; 11.CO.5.223; 11.CO.5.240; 11.CO.5.244; 11.CO.5.243;11.CO.5.247; 11.CO.7.157; 11.CO.7.158; 11.CO.7.196; 11.CO.7.223;11.CO.7.240; 11.CO.7.244; 11.CO.7.243; 11.CO.7.247; 11.CO.15.157;11.CO.15.158; 11.CO.15.196; 11.CO.15.223; 11.CO.15.240; 11.CO.15.244;11.CO.15.243; 11.CO.15.247; 11.CO.16.157; 11.CO.16.158; 11.CO.16.196;11.CO.16.223; 11.CO.16.240; 11.CO.16.244; 11.CO.16.243; 11.CO.16.247;11.CO.18.157; 11.CO.18.158; 11.CO.18.196; 11.CO.18.223; 11.CO.18.240;11.CO.18.244; 11.CO.18.243; 11.CO.18.247; 11.CO.26.157; 11.CO.26.158;11.CO.26.196; 11.CO.26.223; 11.CO.26.240; 11.CO.26.244; 11.CO.26.243;11.CO.26.247; 11.CO.27.157; 11.CO.27.158; 11.CO.27.196; 11.CO.27.223;11.CO.27.240; 11.CO.27.244; 11.CO.27.243; 11.CO.27.247; 11.CO.29.157;11.CO.29.158; 11.CO.29.196; 11.CO.29.223; 11.CO.29.240; 11.CO.29.244;11.CO.29.243; 11.CO.29.247; 11.CO.54.157; 11.CO.54.158; 11.CO.54.196;11.CO.54.223; 11.CO.54.240; 11.CO.54.244; 11.CO.54.243; 11.CO.54.247;11.CO.55.157; 11.CO.55.158; 11.CO.55.196; 11.CO.55.223; 11.CO.55.240;11.CO.55.244; 11.CO.55.243; 11.CO.55.247; 11.CO.56.157; 11.CO.56.158;11.CO.56.196; 11.CO.56.223; 11.CO.56.240; 11.CO.56.244; 11.CO.56.243;11.CO.56.247; 11.CO.157.157; 11.CO.157.158; 11.CO.157.196;11.CO.157.223; 11.CO.157.240; 11.CO.157.244; 11.CO.157.243;11.CO.157.247; 11.CO.196.157; 11.CO.196.158; 11.CO.196.196;11.CO.196.223; 11.CO.196.240; 11.CO.196.244; 11.CO.196.243;11.CO.196.247; 11.CO.223.157; 11.CO.223.158; 11.CO.223.196;11.CO.223.223; 11.CO.223.240; 11.CO.223.244; 11.CO.223.243;11.CO.223.247; 11.CO.240.157; 11.CO.240.158; 11.CO.240.196;11.CO.240.223; 11.CO.240.240; 11.CO.240.244; 11.CO.240.243;11.CO.240.247; 11.CO.244.157; 11.CO.244.158; 11.CO.244.196;11.CO.244.223; 11.CO.244.240; 11.CO.244.244; 11.CO.244.243;11.CO.244.247; 11.CO.247.157; 11.CO.247.158; 11.CO.247.196;11.CO.247.223; 11.CO.247.240; 11.CO.247.244; 11.CO.247.243;11.CO.247.247; Prodrugs of 12.AH 12.AH.4.157; 12.AH.4.158; 12.AH.4.196;12.AH.4.223; 12.AH.4.240; 12.AH.4.244; 12.AH.4.243; 12.AH.4.247;12.AH.5.157; 12.AH.5.158; 12.AH.5.196; 12.AH.5.223; 12.AH.5.240;12.AH.5.244; 12.AH.5.243; 12.AH.5.247; 12.AH.7.157; 12.AH.7.158;12.AH.7.196; 12.AH.7.223; 12.AH.7.240; 12.AH.7.244; 12.AH.7.243;12.AH.7.247; 12.AH.15.157; 12.AH.15.158; 12.AH.15.196; 12.AH.15.223;12.AH.15.240; 12.AH.15.244; 12.AH.15.243; 12.AH.15.247; 12.AH.16.157;12.AH.16.158; 12.AH.16.196; 12.AH.16.223; 12.AH.16.240; 12.AH.16.244;12.AH.16.243; 12.AH.16.247; 12.AH.18.157; 12.AH.18.158; 12.AH.18.196;12.AH.18.223; 12.AH.18.240; 12.AH.18.244; 12.AH.18.243; 12.AH.18.247;12.AH.26.157; 12.AH.26.158; 12.AH.26.196; 12.AH.26.223; 12.AH.26.240;12.AH.26.244; 12.AH.26.243; 12.AH.26.247; 12.AH.27.157; 12.AH.27.158;12.AH.27.196; 12.AH.27.223; 12.AH.27.240; 12.AH.27.244; 12.AH.27.243;12.AH.27.247; 12.AH.29.157; 12.AH.29.158; 12.AH.29.196; 12.AH.29.223;12.AH.29.240; 12.AH.29.244; 12.AH.29.243; 12.AH.29.247; 12.AH.54.157;12.AH.54.158; 12.AH.54.196; 12.AH.54.223; 12.AH.54.240; 12.AH.54.244;12.AH.54.243; 12.AH.54.247; 12.AH.55.157; 12.AH.55.158; 12.AH.55.196;12.AH.55.223; 12.AH.55.240; 12.AH.55.244; 12.AH.55.243; 12.AH.55.247;12.AH.56.157; 12.AH.56.158; 12.AH.56.196; 12.AH.56.223; 12.AH.56.240;12.AH.56.244; 12.AH.56.243; 12.AH.56.247; 12.AH.157.157; 12.AH.157.158;12.AH.157.196; 12.AH.157.223; 12.AH.157.240; 12.AH.157.244;12.AH.157.243; 12.AH.157.247; 12.AH.196.157; 12.AH.196.158;12.AH.196.196; 12.AH.196.223; 12.AH.196.240; 12.AH.196.244;12.AH.196.243; 12.AH.196.247; 12.AH.223.157; 12.AH.223.158;12.AH.223.196; 12.AH.223.223; 12.AH.223.240; 12.AH.223.244;12.AH.223.243; 12.AH.223.247; 12.AH.240.157; 12.AH.240.158;12.AH.240.196; 12.AH.240.223; 12.AH.240.240; 12.AH.240.244;12.AH.240.243; 12.AH.240.247; 12.AH.244.157; 12.AH.244.158;12.AH.244.196; 12.AH.244.223; 12.AH.244.240; 12.AH.244.244;12.AH.244.243; 12.AH.244.247; 12.AH.247.157; 12.AH.247.158;12.AH.247.196; 12.AH.247.223; 12.AH.247.240; 12.AH.247.244;12.AH.247.243; 12.AH.247.247; Prodrugs of 12.AJ 12.AJ.4.157;12.AJ.4.158; 12.AJ.4.196; 12.AJ.4.223; 12.AJ.4.240; 12.AJ.4.244;12.AJ.4.243; 12.AJ.4.247; 12.AJ.5.157; 12.AJ.5.158; 12.AJ.5.196;12.AJ.5.223; 12.AJ.5.240; 12.AJ.5.244; 12.AJ.5.243; 12.AJ.5.247;12.AJ.7.157; 12.AJ.7.158; 12.AJ.7.196; 12.AJ.7.223; 12.AJ.7.240;12.AJ.7.244; 12.AJ.7.243; 12.AJ.7.247; 12.AJ.15.157; 12.AJ.15.158;12.AJ.15.196; 12.AJ.15.223; 12.AJ.15.240; 12.AJ.15.244; 12.AJ.15.243;12.AJ.15.247; 12.AJ.16.157; 12.AJ.16.158; 12.AJ.16.196; 12.AJ.16.223;12.AJ.16.240; 12.AJ.16.244; 12.AJ.16.243; 12.AJ.16.247; 12.AJ.18.157;12.AJ.18.158; 12.AJ.18.196; 12.AJ.18.223; 12.AJ.18.240; 12.AJ.18.244;12.AJ.18.243; 12.AJ.18.247; 12.AJ.26.157; 12.AJ.26.158; 12.AJ.26.196;12.AJ.26.223; 12.AJ.26.240; 12.AJ.26.244; 12.AJ.26.243; 12.AJ.26.247;12.AJ.27.157; 12.AJ.27.158; 12.AJ.27.196; 12.AJ.27.223; 12.AJ.27.240;12.AJ.27.244; 12.AJ.27.243; 12.AJ.27.247; 12.AJ.29.157; 12.AJ.29.158;12.AJ.29.196; 12.AJ.29.223; 12.AJ.29.240; 12.AJ.29.244; 12.AJ.29.243;12.AJ.29.247; 12.AJ.54.157; 12.AJ.54.158; 12.AJ.54.196; 12.AJ.54.223;12.AJ.54.240; 12.AJ.54.244; 12.AJ.54.243; 12.AJ.54.247; 12.AJ.55.157;12.AJ.55.158; 12.AJ.55.196; 12.AJ.55.223; 12.AJ.55.240; 12.AJ.55.244;12.AJ.55.243; 12.AJ.55.247; 12.AJ.56.157; 12.AJ.56.158; 12.AJ.56.196;12.AJ.56.223; 12.AJ.56.240; 12.AJ.56.244; 12.AJ.56.243; 12.AJ.56.247;12.AJ.157.157; 12.AJ.157.158; 12.AJ.157.196; 12.AJ.157.223;12.AJ.157.240; 12.AJ.157.244; 12.AJ.157.243; 12.AJ.157.247;12.AJ.196.157; 12.AJ.196.158; 12.AJ.196.196; 12.AJ.196.223;12.AJ.196.240; 12.AJ.196.244; 12.AJ.196.243; 12.AJ.196.247;12.AJ.223.157; 12.AJ.223.158; 12.AJ.223.196; 12.AJ.223.223;12.AJ.223.240; 12.AJ.223.244; 12.AJ.223.243; 12.AJ.223.247;12.AJ.240.157; 12.AJ.240.158; 12.AJ.240.196; 12.AJ.240.223;12.AJ.240.240; 12.AJ.240.244; 12.AJ.240.243; 12.AJ.240.247;12.AJ.244.157; 12.AJ.244.158; 12.AJ.244.196; 12.AJ.244.223;12.AJ.244.240; 12.AJ.244.244; 12.AJ.244.243; 12.AJ.244.247;12.AJ.247.157; 12.AJ.247.158; 12.AJ.247.196; 12.AJ.247.223;12.AJ.247.240; 12.AJ.247.244; 12.AJ.247.243; 12.AJ.247.247; Prodrugs of12.AN 12.AN.4.157; 12.AN.4.158; 12.AN.4.196; 12.AN.4.223; 12.AN.4.240;12.AN.4.244; 12.AN.4.243; 12.AN.4.247; 12.AN.5.157; 12.AN.5.158;12.AN.5.196; 12.AN.5.223; 12.AN.5.240; 12.AN.5.244; 12.AN.5.243;12.AN.5.247; 12.AN.7.157; 12.AN.7.158; 12.AN.7.196; 12.AN.7.223;12.AN.7.240; 12.AN.7.244; 12.AN.7.243; 12.AN.7.247; 12.AN.15.157;12.AN.15.158; 12.AN.15.196; 12.AN.15.223; 12.AN.15.240; 12.AN.15.244;12.AN.15.243; 12.AN.15.247; 12.AN.16.157; 12.AN.16.158; 12.AN.16.196;12.AN.16.223; 12.AN.16.240; 12.AN.16.244; 12.AN.16.243; 12.AN.16.247;12.AN.18.157; 12.AN.18.158; 12.AN.18.196; 12.AN.18.223; 12.AN.18.240;12.AN.18.244; 12.AN.18.243; 12.AN.18.247; 12.AN.26.157; 12.AN.26.158;12.AN.26.196; 12.AN.26.223; 12.AN.26.240; 12.AN.26.244; 12.AN.26.243;12.AN.26.247; 12.AN.27.157; 12.AN.27.158; 12.AN.27.196; 12.AN.27.223;12.AN.27.240; 12.AN.27.244; 12.AN.27.243; 12.AN.27.247; 12.AN.29.157;12.AN.29.158; 12.AN.29.196; 12.AN.29.223; 12.AN.29.240; 12.AN.29.244;12.AN.29.243; 12.AN.29.247; 12.AN.54.157; 12.AN.54.158; 12.AN.54.196;12.AN.54.223; 12.AN.54.240; 12.AN.54.244; 12.AN.54.243; 12.AN.54.247;12.AN.55.157; 12.AN.55.158; 12.AN.55.196; 12.AN.55.223; 12.AN.55.240;12.AN.55.244; 12.AN.55.243; 12.AN.55.247; 12.AN.56.157; 12.AN.56.158;12.AN.56.196; 12.AN.56.223; 12.AN.56.240; 12.AN.56.244; 12.AN.56.243;12.AN.56.247; 12.AN.157.157; 12.AN.157.158; 12.AN.157.196;12.AN.157.223; 12.AN.157.240; 12.AN.157.244; 12.AN.157.243;12.AN.157.247; 12.AN.196.157; 12.AN.196.158; 12.AN.196.196;12.AN.196.223; 12.AN.196.240; 12.AN.196.244; 12.AN.196.243;12.AN.196.247; 12.AN.223.157; 12.AN.223.158; 12.AN.223.196;12.AN.223.223; 12.AN.223.240; 12.AN.223.244; 12.AN.223.243;12.AN.223.247; 12.AN.240.157; 12.AN.240.158; 12.AN.240.196;12.AN.240.223; 12.AN.240.240; 12.AN.240.244; 12.AN.240.243;12.AN.240.247; 12.AN.244.157; 12.AN.244.158; 12.AN.244.196;12.AN.244.223; 12.AN.244.240; 12.AN.244.244; 12.AN.244.243;12.AN.244.247; 12.AN.247.157; 12.AN.247.158; 12.AN.247.196;12.AN.247.223; 12.AN.247.240; 12.AN.247.244; 12.AN.247.243;12.AN.247.247; Prodrugs of 12.AP 12.AP.4.157; 12.AP.4.158; 12.AP.4.196;12.AP.4.223; 12.AP.4.240; 12.AP.4.244; 12.AP.4.243; 12.AP.4.247;12.AP.5.157; 12.AP.5.158; 12.AP.5.196; 12.AP.5.223; 12.AP.5.240;12.AP.5.244; 12.AP.5.243; 12.AP.5.247; 12.AP.7.157; 12.AP.7.158;12.AP.7.196; 12.AP.7.223; 12.AP.7.240; 12.AP.7.244; 12.AP.7.243;12.AP.7.247; 12.AP.15.157; 12.AP.15.158; 12.AP.15.196; 12.AP.15.223;12.AP.15.240; 12.AP.15.244; 12.AP.15.243; 12.AP.15.247; 12.AP.16.157;12.AP.16.158; 12.AP.16.196; 12.AP.16.223; 12.AP.16.240; 12.AP.16.244;12.AP.16.243; 12.AP.16.247; 12.AP.18.157; 12.AP.18.158; 12.AP.18.196;12.AP.18.223; 12.AP.18.240; 12.AP.18.244; 12.AP.18.243; 12.AP.18.247;12.AP.26.157; 12.AP.26.158; 12.AP.26.196; 12.AP.26.223; 12.AP.26.240;12.AP.26.244; 12.AP.26.243; 12.AP.26.247; 12.AP.27.157; 12.AP.27.158;12.AP.27.196; 12.AP.27.223; 12.AP.27.240; 12.AP.27.244; 12.AP.27.243;12.AP.27.247; 12.AP.29.157; 12.AP.29.158; 12.AP.29.196; 12.AP.29.223;12.AP.29.240; 12.AP.29.244; 12.AP.29.243; 12.AP.29.247; 12.AP.54.157;12.AP.54.158; 12.AP.54.196; 12.AP.54.223; 12.AP.54.240; 12.AP.54.244;12.AP.54.243; 12.AP.54.247; 12.AP.55.157; 12.AP.55.158; 12.AP.55.196;12.AP.55.223; 12.AP.55.240; 12.AP.55.244; 12.AP.55.243; 12.AP.55.247;12.AP.56.157; 12.AP.56.158; 12.AP.56.196; 12.AP.56.223; 12.AP.56.240;12.AP.56.244; 12.AP.56.243; 12.AP.56.247; 12.AP.157.157; 12.AP.157.158;12.AP.157.196; 12.AP.157.223; 12.AP.157.240; 12.AP.157.244;12.AP.157.243; 12.AP.157.247; 12.AP.196.157; 12.AP.196.158;12.AP.196.196; 12.AP.196.223; 12.AP.196.240; 12.AP.196.244;12.AP.196.243; 12.AP.196.247; 12.AP.223.157; 12.AP.223.158;12.AP.223.196; 12.AP.223.223; 12.AP.223.240; 12.AP.223.244;12.AP.223.243; 12.AP.223.247; 12.AP.240.157; 12.AP.240.158;12.AP.240.196; 12.AP.240.223; 12.AP.240.240; 12.AP.240.244;12.AP.240.243; 12.AP.240.247; 12.AP.244.157; 12.AP.244.158;12.AP.244.196; 12.AP.244.223; 12.AP.244.240; 12.AP.244.244;12.AP.244.243; 12.AP.244.247; 12.AP.247.157; 12.AP.247.158;12.AP.247.196; 12.AP.247.223; 12.AP.247.240; 12.AP.247.244;12.AP.247.243; 12.AP.247.247; Prodrugs of 12.AZ 12.AZ.4.157;12.AZ.4.158; 12.AZ.4.196; 12.AZ.4.223; 12.AZ.4.240; 12.AZ.4.244;12.AZ.4.243; 12.AZ.4.247; 12.AZ.5.157; 12.AZ.5.158; 12.AZ.5.196;12.AZ.5.223; 12.AZ.5.240; 12.AZ.5.244; 12.AZ.5.243; 12.AZ.5.247;12.AZ.7.157; 12.AZ.7.158; 12.AZ.7.196; 12.AZ.7.223; 12.AZ.7.240;12.AZ.7.244; 12.AZ.7.243; 12.AZ.7.247; 12.AZ.15.157; 12.AZ.15.158;12.AZ.15.196; 12.AZ.15.223; 12.AZ.15.240; 12.AZ.15.244; 12.AZ.15.243;12.AZ.15.247; 12.AZ.16.157; 12.AZ.16.158; 12.AZ.16.196; 12.AZ.16.223;12.AZ.16.240; 12.AZ.16.244; 12.AZ.16.243; 12.AZ.16.247; 12.AZ.18.157;12.AZ.18.158; 12.AZ.18.196; 12.AZ.18.223; 12.AZ.18.240; 12.AZ.18.244;12.AZ.18.243; 12.AZ.18.247; 12.AZ.26.157; 12.AZ.26.158; 12.AZ.26.196;12.AZ.26.223; 12.AZ.26.240; 12.AZ.26.244; 12.AZ.26.243; 12.AZ.26.247;12.AZ.27.157; 12.AZ.27.158; 12.AZ.27.196; 12.AZ.27.223; 12.AZ.27.240;12.AZ.27.244; 12.AZ.27.243; 12.AZ.27.247; 12.AZ.29.157; 12.AZ.29.158;12.AZ.29.196; 12.AZ.29.223; 12.AZ.29.240; 12.AZ.29.244; 12.AZ.29.243;12.AZ.29.247; 12.AZ.54.157; 12.AZ.54.158; 12.AZ.54.196; 12.AZ.54.223;12.AZ.54.240; 12.AZ.54.244; 12.AZ.54.243; 12.AZ.54.247; 12.AZ.55.157;12.AZ.55.158; 12.AZ.55.196; 12.AZ.55.223; 12.AZ.55.240; 12.AZ.55.244;12.AZ.55.243; 12.AZ.55.247; 12.AZ.56.157; 12.AZ.56.158; 12.AZ.56.196;12.AZ.56.223; 12.AZ.56.240; 12.AZ.56.244; 12.AZ.56.243; 12.AZ.56.247;12.AZ.157.157; 12.AZ.157.158; 12.AZ.157.196; 12.AZ.157.223;12.AZ.157.240; 12.AZ.157.244; 12.AZ.157.243; 12.AZ.157.247;12.AZ.196.157; 12.AZ.196.158; 12.AZ.196.196; 12.AZ.196.223;12.AZ.196.240; 12.AZ.196.244; 12.AZ.196.243; 12.AZ.196.247;12.AZ.223.157; 12.AZ.223.158; 12.AZ.223.196; 12.AZ.223.223;12.AZ.223.240; 12.AZ.223.244; 12.AZ.223.243; 12.AZ.223.247;12.AZ.240.157; 12.AZ.240.158; 12.AZ.240.196; 12.AZ.240.223;12.AZ.240.240; 12.AZ.240.244; 12.AZ.240.243; 12.AZ.240.247;12.AZ.244.157; 12.AZ.244.158; 12.AZ.244.196; 12.AZ.244.223;12.AZ.244.240; 12.AZ.244.244; 12.AZ.244.243; 12.AZ.244.247;12.AZ.247.157; 12.AZ.247.158; 12.AZ.247.196; 12.AZ.247.223;12.AZ.247.240; 12.AZ.247.244; 12.AZ.247.243; 12.AZ.247.247; Prodrugs of12.BF 12.BF.4.157; 12.BF.4.158; 12.BF.4.196; 12.BF.4.223; 12.BF.4.240;12.BF.4.244; 12.BF.4.243; 12.BF.4.247; 12.BF.5.157; 12.BF.5.158;12.BF.5.196; 12.BF.5.223; 12.BF.5.240; 12.BF.5.244; 12.BF.5.243;12.BF.5.247; 12.BF.7.157; 12.BF.7.158; 12.BF.7.196; 12.BF.7.223;12.BF.7.240; 12.BF.7.244; 12.BF.7.243; 12.BF.7.247; 12.BF.15.157;12.BF.15.158; 12.BF.15.196; 12.BF.15.223; 12.BF.15.240; 12.BF.15.244;12.BF.15.243; 12.BF.15.247; 12.BF.16.157; 12.BF.16.158; 12.BF.16.196;12.BF.16.223; 12.BF.16.240; 12.BF.16.244; 12.BF.16.243; 12.BF.16.247;12.BF.18.157; 12.BF.18.158; 12.BF.18.196; 12.BF.18.223; 12.BF.18.240;12.BF.18.244; 12.BF.18.243; 12.BF.18.247; 12.BF.26.157; 12.BF.26.158;12.BF.26.196; 12.BF.26.223; 12.BF.26.240; 12.BF.26.244; 12.BF.26.243;12.BF.26.247; 12.BF.27.157; 12.BF.27.158; 12.BF.27.196; 12.BF.27.223;12.BF.27.240; 12.BF.27.244; 12.BF.27.243; 12.BF.27.247; 12.BF.29.157;12.BF.29.158; 12.BF.29.196; 12.BF.29.223; 12.BF.29.240; 12.BF.29.244;12.BF.29.243; 12.BF.29.247; 12.BF.54.157; 12.BF.54.158; 12.BF.54.196;12.BF.54.223; 12.BF.54.240; 12.BF.54.244; 12.BF.54.243; 12.BF.54.247;12.BF.55.157; 12.BF.55.158; 12.BF.55.196; 12.BF.55.223; 12.BF.55.240;12.BF.55.244; 12.BF.55.243; 12.BF.55.247; 12.BF.56.157; 12.BF.56.158;12.BF.56.196; 12.BF.56.223; 12.BF.56.240; 12.BF.56.244; 12.BF.56.243;12.BF.56.247; 12.BF.157.157; 12.BF.157.158; 12.BF.157.196;12.BF.157.223; 12.BF.157.240; 12.BF.157.244; 12.BF.157.243;12.BF.157.247; 12.BF.196.157; 12.BF.196.158; 12.BF.196.196;12.BF.196.223; 12.BF.196.240; 12.BF.196.244; 12.BF.196.243;12.BF.196.247; 12.BF.223.157; 12.BF.223.158; 12.BF.223.196;12.BF.223.223; 12.BF.223.240; 12.BF.223.244; 12.BF.223.243;12.BF.223.247; 12.BF.240.157; 12.BF.240.158; 12.BF.240.196;12.BF.240.223; 12.BF.240.240; 12.BF.240.244; 12.BF.240.243;12.BF.240.247; 12.BF.244.157; 12.BF.244.158; 12.BF.244.196;12.BF.244.223; 12.BF.244.240; 12.BF.244.244; 12.BF.244.243;12.BF.244.247; 12.BF.247.157; 12.BF.247.158; 12.BF.247.196;12.BF.247.223; 12.BF.247.240; 12.BF.247.244; 12.BF.247.243;12.BF.247.247; Prodrugs of 12.CI 12.CI.4.157; 12.CI.4.158; 12.CI.4.196;12.CI.4.223; 12.CI.4.240; 12.CI.4.244; 12.CI.4.243; 12.CI.4.247;12.CI.5.157; 12.CI.5.158; 12.CI.5.196; 12.CI.5.223; 12.CI.5.240;12.CI.5.244; 12.CI.5.243; 12.CI.5.247; 12.CI.7.157; 12.CI.7.158;12.CI.7.196; 12.CI.7.223; 12.CI.7.240; 12.CI.7.244; 12.CI.7.243;12.CI.7.247; 12.CI.15.157; 12.CI.15.158; 12.CI.15.196; 12.CI.15.223;12.CI.15.240; 12.CI.15.244; 12.CI.15.243; 12.CI.15.247; 12.CI.16.157;12.CI.16.158; 12.CI.16.196; 12.CI.16.223; 12.CI.16.240; 12.CI.16.244;12.CI.16.243; 12.CI.16.247; 12.CI.18.157; 12.CI.18.158; 12.CI.18.196;12.CI.18.223; 12.CI.18.240; 12.CI.18.244; 12.CI.18.243; 12.CI.18.247;12.CI.26.157; 12.CI.26.158; 12.CI.26.196; 12.CI.26.223; 12.CI.26.240;12.CI.26.244; 12.CI.26.243; 12.CI.26.247; 12.CI.27.157; 12.CI.27.158;12.CI.27.196; 12.CI.27.223; 12.CI.27.240; 12.CI.27.244; 12.CI.27.243;12.CI.27.247; 12.CI.29.157; 12.CI.29.158; 12.CI.29.196; 12.CI.29.223;12.CI.29.240; 12.CI.29.244; 12.CI.29.243; 12.CI.29.247; 12.CI.54.157;12.CI.54.158; 12.CI.54.196; 12.CI.54.223; 12.CI.54.240; 12.CI.54.244;12.CI.54.243; 12.CI.54.247; 12.CI.55.157; 12.CI.55.158; 12.CI.55.196;12.CI.55.223; 12.CI.55.240; 12.CI.55.244; 12.CI.55.243; 12.CI.55.247;12.CI.56.157; 12.CI.56.158; 12.CI.56.196; 12.CI.56.223; 12.CI.56.240;12.CI.56.244; 12.CI.56.243; 12.CI.56.247; 12.CI.157.157; 12.CI.157.158;12.CI.157.196; 12.CI.157.223; 12.CI.157.240; 12.CI.157.244;12.CI.157.243; 12.CI.157.247; 12.CI.196.157; 12.CI.196.158;12.CI.196.196; 12.CI.196.223; 12.CI.196.240; 12.CI.196.244;12.CI.196.243; 12.CI.196.247; 12.CI.223.157; 12.CI.223.158;12.CI.223.196; 12.CI.223.223; 12.CI.223.240; 12.CI.223.244;12.CI.223.243; 12.CI.223.247; 12.CI.240.157; 12.CI.240.158;12.CI.240.196; 12.CI.240.223; 12.CI.240.240; 12.CI.240.244;12.CI.240.243; 12.CI.240.247; 12.CI.244.157; 12.CI.244.158;12.CI.244.196; 12.CI.244.223; 12.CI.244.240; 12.CI.244.244;12.CI.244.243; 12.CI.244.247; 12.CI.247.157; 12.CI.247.158;12.CI.247.196; 12.CI.247.223; 12.CI.247.240; 12.CI.247.244;12.CI.247.243; 12.CI.247.247; Prodrugs of 12.CO 12.CO.4.157;12.CO.4.158; 12.CO.4.196; 12.CO.4.223; 12.CO.4.240; 12.CO.4.244;12.CO.4.243; 12.CO.4.247; 12.CO.5.157; 12.CO.5.158; 12.CO.5.196;12.CO.5.223; 12.CO.5.240; 12.CO.5.244; 12.CO.5.243; 12.CO.5.247;12.CO.7.157; 12.CO.7.158; 12.CO.7.196; 12.CO.7.223; 12.CO.7.240;12.CO.7.244; 12.CO.7.243; 12.CO.7.247; 12.CO.15.157; 12.CO.15.158;12.CO.15.196; 12.CO.15.223; 12.CO.15.240; 12.CO.15.244; 12.CO.15.243;12.CO.15.247; 12.CO.16.157; 12.CO.16.158; 12.CO.16.196; 12.CO.16.223;12.CO.16.240; 12.CO.16.244; 12.CO.16.243; 12.CO.16.247; 12.CO.18.157;12.CO.18.158; 12.CO.18.196; 12.CO.18.223; 12.CO.18.240; 12.CO.18.244;12.CO.18.243; 12.CO.18.247; 12.CO.26.157; 12.CO.26.158; 12.CO.26.196;12.CO.26.223; 12.CO.26.240; 12.CO.26.244; 12.CO.26.243; 12.CO.26.247;12.CO.27.157; 12.CO.27.158; 12.CO.27.196; 12.CO.27.223; 12.CO.27.240;12.CO.27.244; 12.CO.27.243; 12.CO.27.247; 12.CO.29.157; 12.CO.29.158;12.CO.29.196; 12.CO.29.223; 12.CO.29.240; 12.CO.29.244; 12.CO.29.243;12.CO.29.247; 12.CO.54.157; 12.CO.54.158; 12.CO.54.196; 12.CO.54.223;12.CO.54.240; 12.CO.54.244; 12.CO.54.243; 12.CO.54.247; 12.CO.55.157;12.CO.55.158; 12.CO.55.196; 12.CO.55.223; 12.CO.55.240; 12.CO.55.244;12.CO.55.243; 12.CO.55.247; 12.CO.56.157; 12.CO.56.158; 12.CO.56.196;12.CO.56.223; 12.CO.56.240; 12.CO.56.244; 12.CO.56.243; 12.CO.56.247;12.CO.157.157; 12.CO.157.158; 12.CO.157.196; 12.CO.157.223;12.CO.157.240; 12.CO.157.244; 12.CO.157.243; 12.CO.157.247;12.CO.196.157; 12.CO.196.158; 12.CO.196.196; 12.CO.196.223;12.CO.196.240; 12.CO.196.244; 12.CO.196.243; 12.CO.196.247;12.CO.223.157; 12.CO.223.158; 12.CO.223.196; 12.CO.223.223;12.CO.223.240; 12.CO.223.244; 12.CO.223.243; 12.CO.223.247;12.CO.240.157; 12.CO.240.158; 12.CO.240.196; 12.CO.240.223;12.CO.240.240; 12.CO.240.244; 12.CO.240.243; 12.CO.240.247;12.CO.244.157; 12.CO.244.158; 12.CO.244.196; 12.CO.244.223;12.CO.244.240; 12.CO.244.244; 12.CO.244.243; 12.CO.244.247;12.CO.247.157; 12.CO.247.158; 12.CO.247.196; 12.CO.247.223;12.CO.247.240; 12.CO.247.244; 12.CO.247.243; 12.CO.247.247. Prodrugs of13.B 13.B.228.228; 13.B.228.229; 13.B.228.230; 13.B.228.231;13.B.228.236; 13.B.228.237; 13.B.228.238; 13.B.228.239; 13.B.228.154;13.B.228.157; 13.B.228.166; 13.B.228.169; 13.B.228.172; 13.B.228.175;13.B.228.240; 13.B.228.244; 13.B.229.228; 13.B.229.229; 13.B.229.230;13.B.229.231; 13.B.229.236; 13.B.229.237; 13.B.229.238; 13.B.229.239;13.B.229.154; 13.B.229.157; 13.B.229.166; 13.B.229.169; 13.B.229.172;13.B.229.175; 13.B.229.240; 13.B.229.244; 13.B.230.228; 13.B.230.229;13.B.230.230; 13.B.230.231; 13.B.230.236; 13.B.230.237; 13.B.230.238;13.B.230.239; 13.B.230.154; 13.B.230.157; 13.B.230.166; 13.B.230.169;13.B.230.172; 13.B.230.175; 13.B.230.240; 13.B.230.244; 13.B.231.228;13.B.231.229; 13.B.231.230; 13.B.231.231; 13.B.231.236; 13.B.231.237;13.B.231.238; 13.B.231.239; 13.B.231.154; 13.B.231.157; 13.B.231.166;13.B.231.169; 13.B.231.172; 13.B.231.175; 13.B.231.240; 13.B.231.244;13.B.236.228; 13.B.236.229; 13.B.236.230; 13.B.236.231; 13.B.236.236;13.B.236.237; 13.B.236.238; 13.B.236.239; 13.B.236.154; 13.B.236.157;13.B.236.166; 13.B.236.169; 13.B.236.172; 13.B.236.175; 13.B.236.240;13.B.236.244; 13.B.237.228; 13.B.237.229; 13.B.237.230; 13.B.237.231;13.B.237.236; 13.B.237.237; 13.B.237.238; 13.B.237.239; 13.B.237.154;13.B.237.157; 13.B.237.166; 13.B.237.169; 13.B.237.172; 13.B.237.175;13.B.237.240; 13.B.237.244; 13.B.238.228; 13.B.238.229; 13.B.238.230;13.B.238.231; 13.B.238.236; 13.B.238.237; 13.B.238.238; 13.B.238.239;13.B.238.154; 13.B.238.157; 13.B.238.166; 13.B.238.169; 13.B.238.172;13.B.238.175; 13.B.238.240; 13.B.238.244; 13.B.239.228; 13.B.239.229;13.B.239.230; 13.B.239.231; 13.B.239.236; 13.B.239.237; 13.B.239.238;13.B.239.239; 13.B.239.154; 13.B.239.157; 13.B.239.166; 13.B.239.169;13.B.239.172; 13.B.239.175; 13.B.239.240; 13.B.239.244; 13.B.154.228;13.B.154.229; 13.B.154.230; 13.B.154.231; 13.B.154.236; 13.B.154.237;13.B.154.238; 13.B.154.239; 13.B.154.154; 13.B.154.157; 13.B.154.166;13.B.154.169; 13.B.154.172; 13.B.154.175; 13.B.154.240; 13.B.154.244;13.B.157.228; 13.B.157.229; 13.B.157.230; 13.B.157.231; 13.B.157.236;13.B.157.237; 13.B.157.238; 13.B.157.239; 13.B.157.154; 13.B.157.157;13.B.157.166; 13.B.157.169; 13.B.157.172; 13.B.157.175; 13.B.157.240;13.B.157.244; 13.B.166.228; 13.B.166.229; 13.B.166.230; 13.B.166.231;13.B.166.236; 13.B.166.237; 13.B.166.238; 13.B.166.239; 13.B.166.154;13.B.166.157; 13.B.166.166; 13.B.166.169; 13.B.166.172; 13.B.166.175;13.B.166.240; 13.B.166.244; 13.B.169.228; 13.B.169.229; 13.B.169.230;13.B.169.231; 13.B.169.236; 13.B.169.237; 13.B.169.238; 13.B.169.239;13.B.169.154; 13.B.169.157; 13.B.169.166; 13.B.169.169; 13.B.169.172;13.B.169.175; 13.B.169.240; 13.B.169.244; 13.B.172.228; 13.B.172.229;13.B.172.230; 13.B.172.231; 13.B.172.236; 13.B.172.237; 13.B.172.238;13.B.172.239; 13.B.172.154; 13.B.172.157; 13.B.172.166; 13.B.172.169;13.B.172.172; 13.B.172.175; 13.B.172.240; 13.B.172.244; 13.B.175.228;13.B.175.229; 13.B.175.230; 13.B.175.231; 13.B.175.236; 13.B.175.237;13.B.175.238; 13.B.175.239; 13.B.175.154; 13.B.175.157; 13.B.175.166;13.B.175.169; 13.B.175.172; 13.B.175.175; 13.B.175.240; 13.B.175.244;13.B.240.228; 13.B.240.229; 13.B.240.230; 13.B.240.231; 13.B.240.236;13.B.240.237; 13.B.240.238; 13.B.240.239; 13.B.240.154; 13.B.240.157;13.B.240.166; 13.B.240.169; 13.B.240.172; 13.B.240.175; 13.B.240.240;13.B.240.244; 13.B.244.228; 13.B.244.229; 13.B.244.230; 13.B.244.231;13.B.244.236; 13.B.244.237; 13.B.244.238; 13.B.244.239; 13.B.244.154;13.B.244.157; 13.B.244.166; 13.B.244.169; 13.B.244.172; 13.B.244.175;13.B.244.240; 13.B.244.244; Prodrugs of 13.D 13.D.228.228; 13.D.228.229;13.D.228.230; 13.D.228.231; 13.D.228.236; 13.D.228.237; 13.D.228.238;13.D.228.239; 13.D.228.154; 13.D.228.157; 13.D.228.166; 13.D.228.169;13.D.228.172; 13.D.228.175; 13.D.228.240; 13.D.228.244; 13.D.229.228;13.D.229.229; 13.D.229.230; 13.D.229.231; 13.D.229.236; 13.D.229.237;13.D.229.238; 13.D.229.239; 13.D.229.154; 13.D.229.157; 13.D.229.166;13.D.229.169; 13.D.229.172; 13.D.229.175; 13.D.229.240; 13.D.229.244;13.D.230.228; 13.D.230.229; 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13.U.244.172; 13.U.244.175; 13.U.244.240; 13.U.244.244;Prodrugs of 13.W 13.W.228.228; 13.W.228.229; 13.W.228.230; 13.W.228.231;13.W.228.236; 13.W.228.237; 13.W.228.238; 13.W.228.239; 13.W.228.154;13.W.228.157; 13.W.228.166; 13.W.228.169; 13.W.228.172; 13.W.228.175;13.W.228.240; 13.W.228.244; 13.W.229.228; 13.W.229.229; 13.W.229.230;13.W.229.231; 13.W.229.236; 13.W.229.237; 13.W.229.238; 13.W.229.239;13.W.229.154; 13.W.229.157; 13.W.229.166; 13.W.229.169; 13.W.229.172;13.W.229.175; 13.W.229.240; 13.W.229.244; 13.W.230.228; 13.W.230.229;13.W.230.230; 13.W.230.231; 13.W.230.236; 13.W.230.237; 13.W.230.238;13.W.230.239; 13.W.230.154; 13.W.230.157; 13.W.230.166; 13.W.230.169;13.W.230.172; 13.W.230.175; 13.W.230.240; 13.W.230.244; 13.W.231.228;13.W.231.229; 13.W.231.230; 13.W.231.231; 13.W.231.236; 13.W.231.237;13.W.231.238; 13.W.231.239; 13.W.231.154; 13.W.231.157; 13.W.231.166;13.W.231.169; 13.W.231.172; 13.W.231.175; 13.W.231.240; 13.W.231.244;13.W.236.228; 13.W.236.229; 13.W.236.230; 13.W.236.231; 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13.W.154.175; 13.W.154.240; 13.W.154.244;13.W.157.228; 13.W.157.229; 13.W.157.230; 13.W.157.231; 13.W.157.236;13.W.157.237; 13.W.157.238; 13.W.157.239; 13.W.157.154; 13.W.157.157;13.W.157.166; 13.W.157.169; 13.W.157.172; 13.W.157.175; 13.W.157.240;13.W.157.244; 13.W.166.228; 13.W.166.229; 13.W.166.230; 13.W.166.231;13.W.166.236; 13.W.166.237; 13.W.166.238; 13.W.166.239; 13.W.166.154;13.W.166.157; 13.W.166.166; 13.W.166.169; 13.W.166.172; 13.W.166.175;13.W.166.240; 13.W.166.244; 13.W.169.228; 13.W.169.229; 13.W.169.230;13.W.169.231; 13.W.169.236; 13.W.169.237; 13.W.169.238; 13.W.169.239;13.W.169.154; 13.W.169.157; 13.W.169.166; 13.W.169.169; 13.W.169.172;13.W.169.175; 13.W.169.240; 13.W.169.244; 13.W.172.228; 13.W.172.229;13.W.172.230; 13.W.172.231; 13.W.172.236; 13.W.172.237; 13.W.172.238;13.W.172.239; 13.W.172.154; 13.W.172.157; 13.W.172.166; 13.W.172.169;13.W.172.172; 13.W.172.175; 13.W.172.240; 13.W.172.244; 13.W.175.228;13.W.175.229; 13.W.175.230; 13.W.175.231; 13.W.175.236; 13.W.175.237;13.W.175.238; 13.W.175.239; 13.W.175.154; 13.W.175.157; 13.W.175.166;13.W.175.169; 13.W.175.172; 13.W.175.175; 13.W.175.240; 13.W.175.244;13.W.240.228; 13.W.240.229; 13.W.240.230; 13.W.240.231; 13.W.240.236;13.W.240.237; 13.W.240.238; 13.W.240.239; 13.W.240.154; 13.W.240.157;13.W.240.166; 13.W.240.169; 13.W.240.172; 13.W.240.175; 13.W.240.240;13.W.240.244; 13.W.244.228; 13.W.244.229; 13.W.244.230; 13.W.244.231;13.W.244.236; 13.W.244.237; 13.W.244.238; 13.W.244.239; 13.W.244.154;13.W.244.157; 13.W.244.166; 13.W.244.169; 13.W.244.172; 13.W.244.175;13.W.244.240; 13.W.244.244; Prodrugs of 13.Y 13.Y.228.228; 13.Y.228.229;13.Y.228.230; 13.Y.228.231; 13.Y.228.236; 13.Y.228.237; 13.Y.228.238;13.Y.228.239; 13.Y.228.154; 13.Y.228.157; 13.Y.228.166; 13.Y.228.169;13.Y.228.172; 13.Y.228.175; 13.Y.228.240; 13.Y.228.244; 13.Y.229.228;13.Y.229.229; 13.Y.229.230; 13.Y.229.231; 13.Y.229.236; 13.Y.229.237;13.Y.229.238; 13.Y.229.239; 13.Y.229.154; 13.Y.229.157; 13.Y.229.166;13.Y.229.169; 13.Y.229.172; 13.Y.229.175; 13.Y.229.240; 13.Y.229.244;13.Y.230.228; 13.Y.230.229; 13.Y.230.230; 13.Y.230.231; 13.Y.230.236;13.Y.230.237; 13.Y.230.238; 13.Y.230.239; 13.Y.230.154; 13.Y.230.157;13.Y.230.166; 13.Y.230.169; 13.Y.230.172; 13.Y.230.175; 13.Y.230.240;13.Y.230.244; 13.Y.231.228; 13.Y.231.229; 13.Y.231.230; 13.Y.231.231;13.Y.231.236; 13.Y.231.237; 13.Y.231.238; 13.Y.231.239; 13.Y.231.154;13.Y.231.157; 13.Y.231.166; 13.Y.231.169; 13.Y.231.172; 13.Y.231.175;13.Y.231.240; 13.Y.231.244; 13.Y.236.228; 13.Y.236.229; 13.Y.236.230;13.Y.236.231; 13.Y.236.236; 13.Y.236.237; 13.Y.236.238; 13.Y.236.239;13.Y.236.154; 13.Y.236.157; 13.Y.236.166; 13.Y.236.169; 13.Y.236.172;13.Y.236.175; 13.Y.236.240; 13.Y.236.244; 13.Y.237.228; 13.Y.237.229;13.Y.237.230; 13.Y.237.231; 13.Y.237.236; 13.Y.237.237; 13.Y.237.238;13.Y.237.239; 13.Y.237.154; 13.Y.237.157; 13.Y.237.166; 13.Y.237.169;13.Y.237.172; 13.Y.237.175; 13.Y.237.240; 13.Y.237.244; 13.Y.238.228;13.Y.238.229; 13.Y.238.230; 13.Y.238.231; 13.Y.238.236; 13.Y.238.237;13.Y.238.238; 13.Y.238.239; 13.Y.238.154; 13.Y.238.157; 13.Y.238.166;13.Y.238.169; 13.Y.238.172; 13.Y.238.175; 13.Y.238.240; 13.Y.238.244;13.Y.239.228; 13.Y.239.229; 13.Y.239.230; 13.Y.239.231; 13.Y.239.236;13.Y.239.237; 13.Y.239.238; 13.Y.239.239; 13.Y.239.154; 13.Y.239.157;13.Y.239.166; 13.Y.239.169; 13.Y.239.172; 13.Y.239.175; 13.Y.239.240;13.Y.239.244; 13.Y.154.228; 13.Y.154.229; 13.Y.154.230; 13.Y.154.231;13.Y.154.236; 13.Y.154.237; 13.Y.154.238; 13.Y.154.239; 13.Y.154.154;13.Y.154.157; 13.Y.154.166; 13.Y.154.169; 13.Y.154.172; 13.Y.154.175;13.Y.154.240; 13.Y.154.244; 13.Y.157.228; 13.Y.157.229; 13.Y.157.230;13.Y.157.231; 13.Y.157.236; 13.Y.157.237; 13.Y.157.238; 13.Y.157.239;13.Y.157.154; 13.Y.157.157; 13.Y.157.166; 13.Y.157.169; 13.Y.157.172;13.Y.157.175; 13.Y.157.240; 13.Y.157.244; 13.Y.166.228; 13.Y.166.229;13.Y.166.230; 13.Y.166.231; 13.Y.166.236; 13.Y.166.237; 13.Y.166.238;13.Y.166.239; 13.Y.166.154; 13.Y.166.157; 13.Y.166.166; 13.Y.166.169;13.Y.166.172; 13.Y.166.175; 13.Y.166.240; 13.Y.166.244; 13.Y.169.228;13.Y.169.229; 13.Y.169.230; 13.Y.169.231; 13.Y.169.236; 13.Y.169.237;13.Y.169.238; 13.Y.169.239; 13.Y.169.154; 13.Y.169.157; 13.Y.169.166;13.Y.169.169; 13.Y.169.172; 13.Y.169.175; 13.Y.169.240; 13.Y.169.244;13.Y.172.228; 13.Y.172.229; 13.Y.172.230; 13.Y.172.231; 13.Y.172.236;13.Y.172.237; 13.Y.172.238; 13.Y.172.239; 13.Y.172.154; 13.Y.172.157;13.Y.172.166; 13.Y.172.169; 13.Y.172.172; 13.Y.172.175; 13.Y.172.240;13.Y.172.244; 13.Y.175.228; 13.Y.175.229; 13.Y.175.230; 13.Y.175.231;13.Y.175.236; 13.Y.175.237; 13.Y.175.238; 13.Y.175.239; 13.Y.175.154;13.Y.175.157; 13.Y.175.166; 13.Y.175.169; 13.Y.175.172; 13.Y.175.175;13.Y.175.240; 13.Y.175.244; 13.Y.240.228; 13.Y.240.229; 13.Y.240.230;13.Y.240.231; 13.Y.240.236; 13.Y.240.237; 13.Y.240.238; 13.Y.240.239;13.Y.240.154; 13.Y.240.157; 13.Y.240.166; 13.Y.240.169; 13.Y.240.172;13.Y.240.175; 13.Y.240.240; 13.Y.240.244; 13.Y.244.228; 13.Y.244.229;13.Y.244.230; 13.Y.244.231; 13.Y.244.236; 13.Y.244.237; 13.Y.244.238;13.Y.244.239; 13.Y.244.154; 13.Y.244.157; 13.Y.244.166; 13.Y.244.169;13.Y.244.172; 13.Y.244.175; 13.Y.244.240; 13.Y.244.244; Prodrugs of14.AH 14.AH.4.157; 14.AH.4.158; 14.AH.4.196; 14.AH.4.223; 14.AH.4.240;14.AH.4.244; 14.AH.4.243; 14.AH.4.247; 14.AH.5.157; 14.AH.5.158;14.AH.5.196; 14.AH.5.223; 14.AH.5.240; 14.AH.5.244; 14.AH.5.243;14.AH.5.247; 14.AH.7.157; 14.AH.7.158; 14.AH.7.196; 14.AH.7.223;14.AH.7.240; 14.AH.7.244; 14.AH.7.243; 14.AH.7.247; 14.AH.15.157;14.AH.15.158; 14.AH.15.196; 14.AH.15.223; 14.AH.15.240; 14.AH.15.244;14.AH.15.243; 14.AH.15.247; 14.AH.16.157; 14.AH.16.158; 14.AH.16.196;14.AH.16.223; 14.AH.16.240; 14.AH.16.244; 14.AH.16.243; 14.AH.16.247;14.AH.18.157; 14.AH.18.158; 14.AH.18.196; 14.AH.18.223; 14.AH.18.240;14.AH.18.244; 14.AH.18.243; 14.AH.18.247; 14.AH.26.157; 14.AH.26.158;14.AH.26.196; 14.AH.26.223; 14.AH.26.240; 14.AH.26.244; 14.AH.26.243;14.AH.26.247; 14.AH.27.157; 14.AH.27.158; 14.AH.27.196; 14.AH.27.223;14.AH.27.240; 14.AH.27.244; 14.AH.27.243; 14.AH.27.247; 14.AH.29.157;14.AH.29.158; 14.AH.29.196; 14.AH.29.223; 14.AH.29.240; 14.AH.29.244;14.AH.29.243; 14.AH.29.247; 14.AH.54.157; 14.AH.54.158; 14.AH.54.196;14.AH.54.223; 14.AH.54.240; 14.AH.54.244; 14.AH.54.243; 14.AH.54.247;14.AH.55.157; 14.AH.55.158; 14.AH.55.196; 14.AH.55.223; 14.AH.55.240;14.AH.55.244; 14.AH.55.243; 14.AH.55.247; 14.AH.56.157; 14.AH.56.158;14.AH.56.196; 14.AH.56.223; 14.AH.56.240; 14.AH.56.244; 14.AH.56.243;14.AH.56.247; 14.AH.157.157; 14.AH.157.158; 14.AH.157.196;14.AH.157.223; 14.AH.157.240; 14.AH.157.244; 14.AH.157.243;14.AH.157.247; 14.AH.196.157; 14.AH.196.158; 14.AH.196.196;14.AH.196.223; 14.AH.196.240; 14.AH.196.244; 14.AH.196.243;14.AH.196.247; 14.AH.223.157; 14.AH.223.158; 14.AH.223.196;14.AH.223.223; 14.AH.223.240; 14.AH.223.244; 14.AH.223.243;14.AH.223.247; 14.AH.240.157; 14.AH.240.158; 14.AH.240.196;14.AH.240.223; 14.AH.240.240; 14.AH.240.244; 14.AH.240.243;14.AH.240.247; 14.AH.244.157; 14.AH.244.158; 14.AH.244.196;14.AH.244.223; 14.AH.244.240; 14.AH.244.244; 14.AH.244.243;14.AH.244.247; 14.AH.247.157; 14.AH.247.158; 14.AH.247.196;14.AH.247.223; 14.AH.247.240; 14.AH.247.244; 14.AH.247.243;14.AH.247.247; Prodrugs of 14.AJ 14.AJ.4.157; 14.AJ.4.158; 14.AJ.4.196;14.AJ.4.223; 14.AJ.4.240; 14.AJ.4.244; 14.AJ.4.243; 14.AJ.4.247;14.AJ.5.157; 14.AJ.5.158; 14.AJ.5.196; 14.AJ.5.223; 14.AJ.5.240;14.AJ.5.244; 14.AJ.5.243; 14.AJ.5.247; 14.AJ.7.157; 14.AJ.7.158;14.AJ.7.196; 14.AJ.7.223; 14.AJ.7.240; 14.AJ.7.244; 14.AJ.7.243;14.AJ.7.247; 14.AJ.15.157; 14.AJ.15.158; 14.AJ.15.196; 14.AJ.15.223;14.AJ.15.240; 14.AJ.15.244; 14.AJ.15.243; 14.AJ.15.247; 14.AJ.16.157;14.AJ.16.158; 14.AJ.16.196; 14.AJ.16.223; 14.AJ.16.240; 14.AJ.16.244;14.AJ.16.243; 14.AJ.16.247; 14.AJ.18.157; 14.AJ.18.158; 14.AJ.18.196;14.AJ.18.223; 14.AJ.18.240; 14.AJ.18.244; 14.AJ.18.243; 14.AJ.18.247;14.AJ.26.157; 14.AJ.26.158; 14.AJ.26.196; 14.AJ.26.223; 14.AJ.26.240;14.AJ.26.244; 14.AJ.26.243; 14.AJ.26.247; 14.AJ.27.157; 14.AJ.27.158;14.AJ.27.196; 14.AJ.27.223; 14.AJ.27.240; 14.AJ.27.244; 14.AJ.27.243;14.AJ.27.247; 14.AJ.29.157; 14.AJ.29.158; 14.AJ.29.196; 14.AJ.29.223;14.AJ.29.240; 14.AJ.29.244; 14.AJ.29.243; 14.AJ.29.247; 14.AJ.54.157;14.AJ.54.158; 14.AJ.54.196; 14.AJ.54.223; 14.AJ.54.240; 14.AJ.54.244;14.AJ.54.243; 14.AJ.54.247; 14.AJ.55.157; 14.AJ.55.158; 14.AJ.55.196;14.AJ.55.223; 14.AJ.55.240; 14.AJ.55.244; 14.AJ.55.243; 14.AJ.55.247;14.AJ.56.157; 14.AJ.56.158; 14.AJ.56.196; 14.AJ.56.223; 14.AJ.56.240;14.AJ.56.244; 14.AJ.56.243; 14.AJ.56.247; 14.AJ.157.157; 14.AJ.157.158;14.AJ.157.196; 14.AJ.157.223; 14.AJ.157.240; 14.AJ.157.244;14.AJ.157.243; 14.AJ.157.247; 14.AJ.196.157; 14.AJ.196.158;14.AJ.196.196; 14.AJ.196.223; 14.AJ.196.240; 14.AJ.196.244;14.AJ.196.243; 14.AJ.196.247; 14.AJ.223.157; 14.AJ.223.158;14.AJ.223.196; 14.AJ.223.223; 14.AJ.223.240; 14.AJ.223.244;14.AJ.223.243; 14.AJ.223.247; 14.AJ.240.157; 14.AJ.240.158;14.AJ.240.196; 14.AJ.240.223; 14.AJ.240.240; 14.AJ.240.244;14.AJ.240.243; 14.AJ.240.247; 14.AJ.244.157; 14.AJ.244.158;14.AJ.244.196; 14.AJ.244.223; 14.AJ.244.240; 14.AJ.244.244;14.AJ.244.243; 14.AJ.244.247; 14.AJ.247.157; 14.AJ.247.158;14.AJ.247.196; 14.AJ.247.223; 14.AJ.247.240; 14.AJ.247.244;14.AJ.247.243; 14.AJ.247.247; Prodrugs of 14.AN 14.AN.4.157;14.AN.4.158; 14.AN.4.196; 14.AN.4.223; 14.AN.4.240; 14.AN.4.244;14.AN.4.243; 14.AN.4.247; 14.AN.5.157; 14.AN.5.158; 14.AN.5.196;14.AN.5.223; 14.AN.5.240; 14.AN.5.244; 14.AN.5.243; 14.AN.5.247;14.AN.7.157; 14.AN.7.158; 14.AN.7.196; 14.AN.7.223; 14.AN.7.240;14.AN.7.244; 14.AN.7.243; 14.AN.7.247; 14.AN.15.157; 14.AN.15.158;14.AN.15.196; 14.AN.15.223; 14.AN.15.240; 14.AN.15.244; 14.AN.15.243;14.AN.15.247; 14.AN.16.157; 14.AN.16.158; 14.AN.16.196; 14.AN.16.223;14.AN.16.240; 14.AN.16.244; 14.AN.16.243; 14.AN.16.247; 14.AN.18.157;14.AN.18.158; 14.AN.18.196; 14.AN.18.223; 14.AN.18.240; 14.AN.18.244;14.AN.18.243; 14.AN.18.247; 14.AN.26.157; 14.AN.26.158; 14.AN.26.196;14.AN.26.223; 14.AN.26.240; 14.AN.26.244; 14.AN.26.243; 14.AN.26.247;14.AN.27.157; 14.AN.27.158; 14.AN.27.196; 14.AN.27.223; 14.AN.27.240;14.AN.27.244; 14.AN.27.243; 14.AN.27.247; 14.AN.29.157; 14.AN.29.158;14.AN.29.196; 14.AN.29.223; 14.AN.29.240; 14.AN.29.244; 14.AN.29.243;14.AN.29.247; 14.AN.54.157; 14.AN.54.158; 14.AN.54.196; 14.AN.54.223;14.AN.54.240; 14.AN.54.244; 14.AN.54.243; 14.AN.54.247; 14.AN.55.157;14.AN.55.158; 14.AN.55.196; 14.AN.55.223; 14.AN.55.240; 14.AN.55.244;14.AN.55.243; 14.AN.55.247; 14.AN.56.157; 14.AN.56.158; 14.AN.56.196;14.AN.56.223; 14.AN.56.240; 14.AN.56.244; 14.AN.56.243; 14.AN.56.247;14.AN.157.157; 14.AN.157.158; 14.AN.157.196; 14.AN.157.223;14.AN.157.240; 14.AN.157.244; 14.AN.157.243; 14.AN.157.247;14.AN.196.157; 14.AN.196.158; 14.AN.196.196; 14.AN.196.223;14.AN.196.240; 14.AN.196.244; 14.AN.196.243; 14.AN.196.247;14.AN.223.157; 14.AN.223.158; 14.AN.223.196; 14.AN.223.223;14.AN.223.240; 14.AN.223.244; 14.AN.223.243; 14.AN.223.247;14.AN.240.157; 14.AN.240.158; 14.AN.240.196; 14.AN.240.223;14.AN.240.240; 14.AN.240.244; 14.AN.240.243; 14.AN.240.247;14.AN.244.157; 14.AN.244.158; 14.AN.244.196; 14.AN.244.223;14.AN.244.240; 14.AN.244.244; 14.AN.244.243; 14.AN.244.247;14.AN.247.157; 14.AN.247.158; 14.AN.247.196; 14.AN.247.223;14.AN.247.240; 14.AN.247.244; 14.AN.247.243; 14.AN.247.247; Prodrugs of14.AP 14.AP.4.157; 14.AP.4.158; 14.AP.4.196; 14.AP.4.223; 14.AP.4.240;14.AP.4.244; 14.AP.4.243; 14.AP.4.247; 14.AP.5.157; 14.AP.5.158;14.AP.5.196; 14.AP.5.223; 14.AP.5.240; 14.AP.5.244; 14.AP.5.243;14.AP.5.247; 14.AP.7.157; 14.AP.7.158; 14.AP.7.196; 14.AP.7.223;14.AP.7.240; 14.AP.7.244; 14.AP.7.243; 14.AP.7.247; 14.AP.15.157;14.AP.15.158; 14.AP.15.196; 14.AP.15.223; 14.AP.15.240; 14.AP.15.244;14.AP.15.243; 14.AP.15.247; 14.AP.16.157; 14.AP.16.158; 14.AP.16.196;14.AP.16.223; 14.AP.16.240; 14.AP.16.244; 14.AP.16.243; 14.AP.16.247;14.AP.18.157; 14.AP.18.158; 14.AP.18.196; 14.AP.18.223; 14.AP.18.240;14.AP.18.244; 14.AP.18.243; 14.AP.18.247; 14.AP.26.157; 14.AP.26.158;14.AP.26.196; 14.AP.26.223; 14.AP.26.240; 14.AP.26.244; 14.AP.26.243;14.AP.26.247; 14.AP.27.157; 14.AP.27.158; 14.AP.27.196; 14.AP.27.223;14.AP.27.240; 14.AP.27.244; 14.AP.27.243; 14.AP.27.247; 14.AP.29.157;14.AP.29.158; 14.AP.29.196; 14.AP.29.223; 14.AP.29.240; 14.AP.29.244;14.AP.29.243; 14.AP.29.247; 14.AP.54.157; 14.AP.54.158; 14.AP.54.196;14.AP.54.223; 14.AP.54.240; 14.AP.54.244; 14.AP.54.243; 14.AP.54.247;14.AP.55.157; 14.AP.55.158; 14.AP.55.196; 14.AP.55.223; 14.AP.55.240;14.AP.55.244; 14.AP.55.243; 14.AP.55.247; 14.AP.56.157; 14.AP.56.158;14.AP.56.196; 14.AP.56.223; 14.AP.56.240; 14.AP.56.244; 14.AP.56.243;14.AP.56.247; 14.AP.157.157; 14.AP.157.158; 14.AP.157.196;14.AP.157.223; 14.AP.157.240; 14.AP.157.244; 14.AP.157.243;14.AP.157.247; 14.AP.196.157; 14.AP.196.158; 14.AP.196.196;14.AP.196.223; 14.AP.196.240; 14.AP.196.244; 14.AP.196.243;14.AP.196.247; 14.AP.223.157; 14.AP.223.158; 14.AP.223.196;14.AP.223.223; 14.AP.223.240; 14.AP.223.244; 14.AP.223.243;14.AP.223.247; 14.AP.240.157; 14.AP.240.158; 14.AP.240.196;14.AP.240.223; 14.AP.240.240; 14.AP.240.244; 14.AP.240.243;14.AP.240.247; 14.AP.244.157; 14.AP.244.158; 14.AP.244.196;14.AP.244.223; 14.AP.244.240; 14.AP.244.244; 14.AP.244.243;14.AP.244.247; 14.AP.247.157; 14.AP.247.158; 14.AP.247.196;14.AP.247.223; 14.AP.247.240; 14.AP.247.244; 14.AP.247.243;14.AP.247.247; Prodrugs of 14.AZ 14.AZ.4.157; 14.AZ.4.158; 14.AZ.4.196;14.AZ.4.223; 14.AZ.4.240; 14.AZ.4.244; 14.AZ.4.243; 14.AZ.4.247;14.AZ.5.157; 14.AZ.5.158; 14.AZ.5.196; 14.AZ.5.223; 14.AZ.5.240;14.AZ.5.244; 14.AZ.5.243; 14.AZ.5.247; 14.AZ.7.157; 14.AZ.7.158;14.AZ.7.196; 14.AZ.7.223; 14.AZ.7.240; 14.AZ.7.244; 14.AZ.7.243;14.AZ.7.247; 14.AZ.15.157; 14.AZ.15.158; 14.AZ.15.196; 14.AZ.15.223;14.AZ.15.240; 14.AZ.15.244; 14.AZ.15.243; 14.AZ.15.247; 14.AZ.16.157;14.AZ.16.158; 14.AZ.16.196; 14.AZ.16.223; 14.AZ.16.240; 14.AZ.16.244;14.AZ.16.243; 14.AZ.16.247; 14.AZ.18.157; 14.AZ.18.158; 14.AZ.18.196;14.AZ.18.223; 14.AZ.18.240; 14.AZ.18.244; 14.AZ.18.243; 14.AZ.18.247;14.AZ.26.157; 14.AZ.26.158; 14.AZ.26.196; 14.AZ.26.223; 14.AZ.26.240;14.AZ.26.244; 14.AZ.26.243; 14.AZ.26.247; 14.AZ.27.157; 14.AZ.27.158;14.AZ.27.196; 14.AZ.27.223; 14.AZ.27.240; 14.AZ.27.244; 14.AZ.27.243;14.AZ.27.247; 14.AZ.29.157; 14.AZ.29.158; 14.AZ.29.196; 14.AZ.29.223;14.AZ.29.240; 14.AZ.29.244; 14.AZ.29.243; 14.AZ.29.247; 14.AZ.54.157;14.AZ.54.158; 14.AZ.54.196; 14.AZ.54.223; 14.AZ.54.240; 14.AZ.54.244;14.AZ.54.243; 14.AZ.54.247; 14.AZ.55.157; 14.AZ.55.158; 14.AZ.55.196;14.AZ.55.223; 14.AZ.55.240; 14.AZ.55.244; 14.AZ.55.243; 14.AZ.55.247;14.AZ.56.157; 14.AZ.56.158; 14.AZ.56.196; 14.AZ.56.223; 14.AZ.56.240;14.AZ.56.244; 14.AZ.56.243; 14.AZ.56.247; 14.AZ.157.157; 14.AZ.157.158;14.AZ.157.196; 14.AZ.157.223; 14.AZ.157.240; 14.AZ.157.244;14.AZ.157.243; 14.AZ.157.247; 14.AZ.196.157; 14.AZ.196.158;14.AZ.196.196; 14.AZ.196.223; 14.AZ.196.240; 14.AZ.196.244;14.AZ.196.243; 14.AZ.196.247; 14.AZ.223.157; 14.AZ.223.158;14.AZ.223.196; 14.AZ.223.223; 14.AZ.223.240; 14.AZ.223.244;14.AZ.223.243; 14.AZ.223.247; 14.AZ.240.157; 14.AZ.240.158;14.AZ.240.196; 14.AZ.240.223; 14.AZ.240.240; 14.AZ.240.244;14.AZ.240.243; 14.AZ.240.247; 14.AZ.244.157; 14.AZ.244.158;14.AZ.244.196; 14.AZ.244.223; 14.AZ.244.240; 14.AZ.244.244;14.AZ.244.243; 14.AZ.244.247; 14.AZ.247.157; 14.AZ.247.158;14.AZ.247.196; 14.AZ.247.223; 14.AZ.247.240; 14.AZ.247.244;14.AZ.247.243; 14.AZ.247.247; Prodrugs of 14.BF 14.BF.4.157;14.BF.4.158; 14.BF.4.196; 14.BF.4.223; 14.BF.4.240; 14.BF.4.244;14.BF.4.243; 14.BF.4.247; 14.BF.5.157; 14.BF.5.158; 14.BF.5.196;14.BF.5.223; 14.BF.5.240; 14.BF.5.244; 14.BF.5.243; 14.BF.5.247;14.BF.7.157; 14.BF.7.158; 14.BF.7.196; 14.BF.7.223; 14.BF.7.240;14.BF.7.244; 14.BF.7.243; 14.BF.7.247; 14.BF.15.157; 14.BF.15.158;14.BF.15.196; 14.BF.15.223; 14.BF.15.240; 14.BF.15.244; 14.BF.15.243;14.BF.15.247; 14.BF.16.157; 14.BF.16.158; 14.BF.16.196; 14.BF.16.223;14.BF.16.240; 14.BF.16.244; 14.BF.16.243; 14.BF.16.247; 14.BF.18.157;14.BF.18.158; 14.BF.18.196; 14.BF.18.223; 14.BF.18.240; 14.BF.18.244;14.BF.18.243; 14.BF.18.247; 14.BF.26.157; 14.BF.26.158; 14.BF.26.196;14.BF.26.223; 14.BF.26.240; 14.BF.26.244; 14.BF.26.243; 14.BF.26.247;14.BF.27.157; 14.BF.27.158; 14.BF.27.196; 14.BF.27.223; 14.BF.27.240;14.BF.27.244; 14.BF.27.243; 14.BF.27.247; 14.BF.29.157; 14.BF.29.158;14.BF.29.196; 14.BF.29.223; 14.BF.29.240; 14.BF.29.244; 14.BF.29.243;14.BF.29.247; 14.BF.54.157; 14.BF.54.158; 14.BF.54.196; 14.BF.54.223;14.BF.54.240; 14.BF.54.244; 14.BF.54.243; 14.BF.54.247; 14.BF.55.157;14.BF.55.158; 14.BF.55.196; 14.BF.55.223; 14.BF.55.240; 14.BF.55.244;14.BF.55.243; 14.BF.55.247; 14.BF.56.157; 14.BF.56.158; 14.BF.56.196;14.BF.56.223; 14.BF.56.240; 14.BF.56.244; 14.BF.56.243; 14.BF.56.247;14.BF.157.157; 14.BF.157.158; 14.BF.157.196; 14.BF.157.223;14.BF.157.240; 14.BF.157.244; 14.BF.157.243; 14.BF.157.247;14.BF.196.157; 14.BF.196.158; 14.BF.196.196; 14.BF.196.223;14.BF.196.240; 14.BF.196.244; 14.BF.196.243; 14.BF.196.247;14.BF.223.157; 14.BF.223.158; 14.BF.223.196; 14.BF.223.223;14.BF.223.240; 14.BF.223.244; 14.BF.223.243; 14.BF.223.247;14.BF.240.157; 14.BF.240.158; 14.BF.240.196; 14.BF.240.223;14.BF.240.240; 14.BF.240.244; 14.BF.240.243; 14.BF.240.247;14.BF.244.157; 14.BF.244.158; 14.BF.244.196; 14.BF.244.223;14.BF.244.240; 14.BF.244.244; 14.BF.244.243; 14.BF.244.247;14.BF.247.157; 14.BF.247.158; 14.BF.247.196; 14.BF.247.223;14.BF.247.240; 14.BF.247.244; 14.BF.247.243; 14.BF.247.247; Prodrugs of14.CI 14.CI.4.157; 14.CI.4.158; 14.CI.4.196; 14.CI.4.223; 14.CI.4.240;14.CI.4.244; 14.CI.4.243; 14.CI.4.247; 14.CI.5.157; 14.CI.5.158;14.CI.5.196; 14.CI.5.223; 14.CI.5.240; 14.CI.5.244; 14.CI.5.243;14.CI.5.247; 14.CI.7.157; 14.CI.7.158; 14.CI.7.196; 14.CI.7.223;14.CI.7.240; 14.CI.7.244; 14.CI.7.243; 14.CI.7.247; 14.CI.15.157;14.CI.15.158; 14.CI.15.196; 14.CI.15.223; 14.CI.15.240; 14.CI.15.244;14.CI.15.243; 14.CI.15.247; 14.CI.16.157; 14.CI.16.158; 14.CI.16.196;14.CI.16.223; 14.CI.16.240; 14.CI.16.244; 14.CI.16.243; 14.CI.16.247;14.CI.18.157; 14.CI.18.158; 14.CI.18.196; 14.CI.18.223; 14.CI.18.240;14.CI.18.244; 14.CI.18.243; 14.CI.18.247; 14.CI.26.157; 14.CI.26.158;14.CI.26.196; 14.CI.26.223; 14.CI.26.240; 14.CI.26.244; 14.CI.26.243;14.CI.26.247; 14.CI.27.157; 14.CI.27.158; 14.CI.27.196; 14.CI.27.223;14.CI.27.240; 14.CI.27.244; 14.CI.27.243; 14.CI.27.247; 14.CI.29.157;14.CI.29.158; 14.CI.29.196; 14.CI.29.223; 14.CI.29.240; 14.CI.29.244;14.CI.29.243; 14.CI.29.247; 14.CI.54.157; 14.CI.54.158; 14.CI.54.196;14.CI.54.223; 14.CI.54.240; 14.CI.54.244; 14.CI.54.243; 14.CI.54.247;14.CI.55.157; 14.CI.55.158; 14.CI.55.196; 14.CI.55.223; 14.CI.55.240;14.CI.55.244; 14.CI.55.243; 14.CI.55.247; 14.CI.56.157; 14.CI.56.158;14.CI.56.196; 14.CI.56.223; 14.CI.56.240; 14.CI.56.244; 14.CI.56.243;14.CI.56.247; 14.CI.157.157; 14.CI.157.158; 14.CI.157.196;14.CI.157.223; 14.CI.157.240; 14.CI.157.244; 14.CI.157.243;14.CI.157.247; 14.CI.196.157; 14.CI.196.158; 14.CI.196.196;14.CI.196.223; 14.CI.196.240; 14.CI.196.244; 14.CI.196.243;14.CI.196.247; 14.CI.223.157; 14.CI.223.158; 14.CI.223.196;14.CI.223.223; 14.CI.223.240; 14.CI.223.244; 14.CI.223.243;14.CI.223.247; 14.CI.240.157; 14.CI.240.158; 14.CI.240.196;14.CI.240.223; 14.CI.240.240; 14.CI.240.244; 14.CI.240.243;14.CI.240.247; 14.CI.244.157; 14.CI.244.158; 14.CI.244.196;14.CI.244.223; 14.CI.244.240; 14.CI.244.244; 14.CI.244.243;14.CI.244.247; 14.CI.247.157; 14.CI.247.158; 14.CI.247.196;14.CI.247.223; 14.CI.247.240; 14.CI.247.244; 14.CI.247.243;14.CI.247.247; Prodrugs of 14.CO 14.CO.4.157; 14.CO.4.158; 14.CO.4.196;14.CO.4.223; 14.CO.4.240; 14.CO.4.244; 14.CO.4.243; 14.CO.4.247;14.CO.5.157; 14.CO.5.158; 14.CO.5.196; 14.CO.5.223; 14.CO.5.240;14.CO.5.244; 14.CO.5.243; 14.CO.5.247; 14.CO.7.157; 14.CO.7.158;14.CO.7.196; 14.CO.7.223; 14.CO.7.240; 14.CO.7.244; 14.CO.7.243;14.CO.7.247; 14.CO.15.157; 14.CO.15.158; 14.CO.15.196; 14.CO.15.223;14.CO.15.240; 14.CO.15.244; 14.CO.15.243; 14.CO.15.247; 14.CO.16.157;14.CO.16.158; 14.CO.16.196; 14.CO.16.223; 14.CO.16.240; 14.CO.16.244;14.CO.16.243; 14.CO.16.247; 14.CO.18.157; 14.CO.18.158; 14.CO.18.196;14.CO.18.223; 14.CO.18.240; 14.CO.18.244; 14.CO.18.243; 14.CO.18.247;14.CO.26.157; 14.CO.26.158; 14.CO.26.196; 14.CO.26.223; 14.CO.26.240;14.CO.26.244; 14.CO.26.243; 14.CO.26.247; 14.CO.27.157; 14.CO.27.158;14.CO.27.196; 14.CO.27.223; 14.CO.27.240; 14.CO.27.244; 14.CO.27.243;14.CO.27.247; 14.CO.29.157; 14.CO.29.158; 14.CO.29.196; 14.CO.29.223;14.CO.29.240; 14.CO.29.244; 14.CO.29.243; 14.CO.29.247; 14.CO.54.157;14.CO.54.158; 14.CO.54.196; 14.CO.54.223; 14.CO.54.240; 14.CO.54.244;14.CO.54.243; 14.CO.54.247; 14.CO.55.157; 14.CO.55.158; 14.CO.55.196;14.CO.55.223; 14.CO.55.240; 14.CO.55.244; 14.CO.55.243; 14.CO.55.247;14.CO.56.157; 14.CO.56.158; 14.CO.56.196; 14.CO.56.223; 14.CO.56.240;14.CO.56.244; 14.CO.56.243; 14.CO.56.247; 14.CO.157.157; 14.CO.157.158;14.CO.157.196; 14.CO.157.223; 14.CO.157.240; 14.CO.157.244;14.CO.157.243; 14.CO.157.247; 14.CO.196.157; 14.CO.196.158;14.CO.196.196; 14.CO.196.223; 14.CO.196.240; 14.CO.196.244;14.CO.196.243; 14.CO.196.247; 14.CO.223.157; 14.CO.223.158;14.CO.223.196; 14.CO.223.223; 14.CO.223.240; 14.CO.223.244;14.CO.223.243; 14.CO.223.247; 14.CO.240.157; 14.CO.240.158;14.CO.240.196; 14.CO.240.223; 14.CO.240.240; 14.CO.240.244;14.CO.240.243; 14.CO.240.247; 14.CO.244.157; 14.CO.244.158;14.CO.244.196; 14.CO.244.223; 14.CO.244.240; 14.CO.244.244;14.CO.244.243; 14.CO.244.247; 14.CO.4.157; 14.CO.4.158; 14.CO.4.196;14.CO.4.223; 14.CO.4.240; 14.CO.4.244; 14.CO.4.243; 14.CO.4.247;

All literature and patent citations herein are hereby expresslyincorporated by reference at the locations of their citation.Specifically cited sections or pages of the above cited works areincorporated by reference with specificity. The invention has beendescribed in detail sufficient to allow one of ordinary skill in the artto make and use the subject matter of the following claims. It isapparent that certain modifications of the methods and compositions ofthe following claims can be made within the scope and spirit of theinvention.

In the claims hereinbelow, the subscript and superscripts of a givenvariable are distinct. For example, R₁ is distinct from R¹.

1. A conjugate of formula:[DRUG]-(A⁰)_(nn); wherein: DRUG is a compound of formula 518:

wherein: nn is 1, 2, or 3; A⁰ is A¹, A or W³ with the proviso that theconjugate includes at least one A¹; A¹ is:

A² is:

A³ is:

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x))); Y² is independently a bond, O,N(R^(x)), N(O)(R^(x)), N(OR^(x)), N(O)(OR^(x)), N(N(R^(x))(R^(x))),—S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—; and when Y² joins two phosphorousatoms Y² can also be C(R²)(R²); R^(x) is independently H, R¹, R², W³, aprotecting group, or the formula:

wherein: R¹ is independently H, W³, R² or a protecting group; R¹ isindependently H or alkyl of 1 to 18 carbon atoms; R² is independently H,R¹, R³ or R⁴ wherein each R⁴ is independently substituted with 0 to 3 R³groups or taken together at a carbon atom, two R² groups form a ring of3 to 8 carbons and the ring may be substituted with 0 to 3 R³ groups; R³is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is bound to aheteroatom, then R³ is R^(3c) or R^(3d); R^(3a) is F, Cl, Br, I, —CN, N₃or —NO₂; R^(3b) is Y¹; R^(3c) is R^(x), —N(R^(x))(R^(x)), —SR^(x),—S(O)R^(x), —S(O)₂R^(x), —S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x),—OC(Y¹)OR^(x), —OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), —N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x))); R³ is —C(Y¹)R^(x), —C(Y¹)OR^(x) or—C(Y¹)(N(R^(x))(R^(x))); R⁴ is an alkyl of 1 to 18 carbon atoms, alkenylof 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms; R⁵ is R⁴wherein each R⁴ is substituted with 0 to 3 R³ groups; W³ is W⁴ or W⁵; W⁴is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO_(M2)R⁵, or —SO_(M2)W⁵; W⁵ is carbocyclewherein W⁵ is independently substituted with 0 to 3 R² groups; W⁶ is W³independently substituted with 1, 2, or 3 A3 groups; M2 is 0, 1 or 2;M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; M12b is 0, 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11 or 12; M1a, M1c, and M1d are independently 0 or 1;and M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; or apharmaceutically acceptable salt or solvate thereof.
 2. The conjugate ofclaim 1 which is a compound of formula 42, 43, or 44:


3. The conjugate of claim 1 wherein each A³ is of the formula:


4. The conjugate of claim 1 wherein each A³ is of the formula:

wherein Y^(2b) is O or N(R^(x)).
 5. The conjugate of claim 1 whereineach A³ is of the formula:


6. The conjugate of claim 1 wherein each A³ is of the formula:


7. The conjugate of claim 1 wherein each A³ is of the formula:

wherein Y^(2b) is O or N(R^(x)).
 8. The conjugate of claim 1 whereineach A³ is of the formula:

wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R²groups.
 9. The conjugate of claim 1 wherein each A³ is of the formula:

wherein: Y^(1a) is O or S; Y^(2b) is O or N(R²); and Y^(2c) is O,N(R^(y)) or S.
 10. The conjugate of claim 1 wherein A⁰ is of theformula:

wherein each R is independently alkyl.
 11. A pharmaceutical compositioncomprising a pharmaceutical excipient and a conjugate as described inclaim 1, or a pharmaceutically acceptable salt or solvate thereof.